U.S. patent application number 10/693444 was filed with the patent office on 2004-05-06 for compound.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Berge, Odd-Geir, Claesson, Alf, Swahn, Britt-Marie.
Application Number | 20040087800 10/693444 |
Document ID | / |
Family ID | 26654970 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040087800 |
Kind Code |
A1 |
Claesson, Alf ; et
al. |
May 6, 2004 |
Compound
Abstract
The present invention relates to certain spirooxindole
derivatives of the formula I, and pharmaceutically acceptable salts
thereof, which exhibit good analgesic properties and are
particularly effective in the treatment of chronic pain. 1
Inventors: |
Claesson, Alf; (Ronninge,
SE) ; Swahn, Britt-Marie; (Sodertalje, SE) ;
Berge, Odd-Geir; (Ronninge, SE) |
Correspondence
Address: |
Michael A. Sanzo
Fitch, Even, Tabin & Flannery
Suite 401L
1801 K Street, N.W.
Washington
DC
20006-1201
US
|
Assignee: |
AstraZeneca AB
|
Family ID: |
26654970 |
Appl. No.: |
10/693444 |
Filed: |
October 27, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10693444 |
Oct 27, 2003 |
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09674373 |
Oct 27, 2000 |
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09674373 |
Oct 27, 2000 |
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PCT/SE00/01506 |
Jul 20, 2000 |
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Current U.S.
Class: |
548/147 ;
548/216; 548/301.1 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 25/16 20180101; A61P 35/00 20180101; C07D 471/10 20130101;
A61P 25/04 20180101; A61P 1/06 20180101; A61P 15/00 20180101; C07D
491/10 20130101; A61P 25/08 20180101; A61P 25/20 20180101; A61P
25/34 20180101; A61P 43/00 20180101; C07D 487/10 20130101; A61P
17/02 20180101; A61P 25/00 20180101; A61P 19/02 20180101; A61P
25/14 20180101; A61P 25/36 20180101; A61P 31/18 20180101; A61P
29/00 20180101; A61P 25/28 20180101; A61P 3/10 20180101; A61P 41/00
20180101; A61P 25/32 20180101; A61P 1/14 20180101; A61P 21/02
20180101; A61P 1/04 20180101; A61P 17/04 20180101; A61P 25/30
20180101; A61P 21/00 20180101; A61P 25/06 20180101 |
Class at
Publication: |
548/147 ;
548/216; 548/301.1 |
International
Class: |
C07D 277/60; C07D
235/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 21, 1999 |
SE |
9902762-5 |
Jan 27, 2000 |
SE |
0000263-4 |
Claims
1. A compound of the formula I 16in racemic form or in the form of
an enantiomer, or a pharmaceutically acceptable salt thereof,
wherein R.sup.1 is a) H, b) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, c) C.sub.1-C.sub.6 alkoxy C.sub.2-C.sub.6
alkyl, d) C.sub.1-C.sub.6 alkylthio C.sub.2-C.sub.6 alkyl, e)
halogenated C.sub.1-C.sub.6 alkyl, f) aryl C.sub.1-C.sub.6 alkyl,
g) C.sub.1-C.sub.6 alkenyl, or h) C.sub.1-C.sub.6 cycloalkyl
C.sub.1-C.sub.2 alkyl; R.sup.2 is a) H, b) C.sub.1-C.sub.6 alkyl,
c) C.sub.2-C.sub.4 alkynyl, d) halogen, e) substituted or
unsubstituted carbamoyl, f) substituted or unsubstituted
carbamoyloxy, g) C.sub.1-C.sub.6 alkylcarbonyl, h) C.sub.1-C.sub.6
alkoxycarbonyl, i) C.sub.1-C.sub.6 alkylcarbonyloxy, j)
hydroxy-substituted C.sub.1-C.sub.6 alkyl, k) cyano, l) nitro, m)
amino, n) halogenated C.sub.1-C.sub.6 alkyl, o) halogenated
C.sub.1-C.sub.6 alkoxy, p) halogenated C.sub.1-C.sub.6 alkylthio,
q) C.sub.1-C.sub.6 alkylsulfinyl, r) C.sub.1-C.sub.6 alkylsulfonyl,
s) C.sub.1-C.sub.4 alkylsulfinylalkyl, t) C.sub.1-C.sub.4
alkylsulfonylalkyl, u) C.sub.1-C.sub.6 alkylsulfonylamino, v)
halogenated C.sub.1-C.sub.6 alkylsulfonylamino, w) halogenated
C.sub.1-C.sub.2 alkylsulfonyloxy, x) aminosulfonyl, y)
aminosulfonyloxy, z) aryl, aa) heteroaryl, bb) arylcarbonyl, cc)
heteroarylcarbonyl, dd) arylsulfinyl, ee) heteroarylsulfinyl, ff)
arylsulfonyl, gg) heteroarylsulfonyl, in which any aromatic moiety
is optionally substituted, hh) C.sub.1-C.sub.6 alkylcarbonylamino,
ii) C.sub.1-C.sub.6 alkoxycarbonylamino, jj) C.sub.1-C.sub.6
alkyl-thiocarbonyl, kk) C.sub.1-C.sub.6 alkoxy-thiocarbonyl, ll)
formyl, or mm)alkoxysulfonylamino; R.sup.3 is a) H, b)
C.sub.1-C.sub.6 alkyl, c) halogen, d) C.sub.1-C.sub.6 alkoxy, e)
halogenated C.sub.1-C.sub.4 alkyl, f) halogenated C.sub.1-C.sub.6
alkoxy, g) halogenated C.sub.1-C.sub.6 alkylthio, h)
C.sub.1-C.sub.4 alkylsulfinyl, i) C.sub.1-C.sub.4 alkylsulfonyl, j)
C.sub.1-C.sub.4 alkylsulfinyl C.sub.1-C.sub.6 alkyl, k)
C.sub.1-C.sub.4 alkylsulfonyl C.sub.1-C.sub.6 alkyl, l)
C.sub.1-C.sub.4 alkylsulfonylamino, m)halogenated C.sub.1-C.sub.4
alkylsulfonylamino, n) aminosulfonyl, or o) aminosulfonyloxy;
R.sup.4 is a) H, b) C.sub.1-C.sub.4 alkyl, or c) halogen; R.sup.2
and R.sup.3 may together with the carbon atoms to which they are
attached, form a saturated or unsaturated ring, optionally
containing one or more further heteroatoms, and/or optionally
substituted with one or more substituents selected from halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OH, cyano,
amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2--N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--; Any amino moiety in R.sup.2-R.sup.4 can
obtionally be substituted with one or two C.sub.1-C.sub.6 alkyl
groups which may be part of a ring; Ar is a) benzene, b) pyridine,
c) thiophene, d) pyrazine, e) pyrimidine, f) oxazole, g) thiazole,
h) pyrrole, i) pyrazole, or j) furan; X is a) --NHCO--, b)
--CONH--, c) --NH--SO.sub.2--, d) --SO.sub.2NH--, e) --OCH.sub.2--,
f) --NHCH.sub.2--, or g) --NHCOCH.sub.2--; Y is a) --CH.sub.2--, b)
--CH(C.sub.1-C.sub.6 alkyl)-, c) --C(C.sub.1-C.sub.6 alkyl).sub.2-,
or d) a single bond; Z is a) --CH.sub.2CH.sub.2CH.sub.2--, b)
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, c) --CH.dbd.CHCH.sub.2--, d)
--CH.dbd.CHCH.sub.2CH.sub.2--, or e) --CH.sub.2CH.dbd.CHCH.sub.2--;
provided that when X is --NHCOCH.sub.2-- then Y cannot be
--CH.sub.2--; and excluding the racemic compounds wherein Ar is
benzene, R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single
bond, Z is --CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or
n-propyl.
2. A compound according to claim 1, wherein R.sup.1 is a) H, b)
C.sub.1-C.sub.4 alkyl, c) C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4
alkyl, d) C.sub.1-C.sub.4 alkylthio C.sub.1-C.sub.4 alkyl, e)
fluorinated C.sub.1-C.sub.4 alkyl, f) aryl C.sub.1-C.sub.4 alkyl,
g) C.sub.1-C.sub.4 alkenyl, or h) cyclopropylmethyl; R.sup.2 is a)
H, b) C.sub.1-C.sub.4 alkyl, c) C.sub.2-C.sub.3 alkynyl, d)
halogen, e) substituted or unsubstituted carbamoyl, f) substituted
or unsubstituted carbamoyloxy, g) C.sub.1-C.sub.3 alkylcarbonyl, h)
C.sub.1-C.sub.3 alkoxycarbonyl, i) C.sub.1-C.sub.3
alkylcarbonyloxy, j) hydroxy-substituted C.sub.1-C.sub.3 alkyl, k)
cyano, l) fluorinated C.sub.1-C.sub.3 alkoxy, m) fluorinated
C.sub.1-C.sub.6 alkylthio, n) C.sub.1-C.sub.3 alkylsulfinyl, o)
C.sub.1-C.sub.3 alkylsulfonyl, p) C.sub.1-C.sub.3 alkylsulfinyl
C.sub.1-C.sub.6 alkyl, q) C.sub.1-C.sub.4 alkylsulfonyl
C.sub.1-C.sub.6 alkyl, r) C.sub.1-C.sub.3 alkylsulfonylamino, s)
halogenated C.sub.1-C.sub.3 alkylsulfonylamino, t) sulfamoyl, u)
sulfamoyloxy, v) aryl, w) heteroaryl, x) heteroarylsulfinyl, y)
arylsulfonyl, z) heteroarylsulfonyl, in which any aromatic moiety
is optionally substituted, aa) C.sub.1-C.sub.4 alkylcarbonylamino,
bb) C.sub.1-C.sub.3 alkoxycarbonylamino, cc) C.sub.1-C.sub.3
alkyl-thiocarbonyl, or dd) C.sub.1-C.sub.3 alkoxy-thiocarbonyl;
R.sup.3 is a) H, b) C.sub.1-C.sub.4 alkyl, or c) halogen; R.sup.4
is a) H, b) C.sub.1-C.sub.4 alkyl, or c) halogen, R.sup.2 and
R.sup.3 may together with the carbon atoms to which they are
attached, form a saturated or unsaturated ring, optionally
containing one or more further heteroatoms, and/or optionally
substituted with one or more substituents selected from halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3, OH, cyano,
amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2-N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--; Any amino moiety in R.sup.2-R.sup.4 can
obtionally be substituted with one or two C.sub.1-C.sub.6 alkyl
groups which may be part of a ring; Ar is a) benzene, b) pyridine,
c) thiophene, d) pyrazine, e) pyrimidine, f) oxazole, g) thiazole,
h) pyrrole, i) pyrazole, or j) furan; X is a) --NHCO--, b)
--CONH--, c) --NH--SO.sub.2--, or d) --SO.sub.2NH--; Y is a)
--CH.sub.2--, b) --CH(C.sub.1-C.sub.6 alkyl)--, c)
--C(C.sub.1-C.sub.6 alkyl).sub.2--, or d) a single bond; Z is f)
--CH.sub.2CH.sub.2CH.sub.2--- , g)
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, h) --CH.dbd.CHCH.sub.2--, i)
--CH.dbd.CHCH.sub.2CH.sub.2--, or j) --CH.sub.2CH.dbd.CHCH.sub.2--;
provided that when X is --NHCOCH.sub.2-- then Y cannot be
--CH.sub.2--; and excluding the racemic compounds wherein Ar is
benzene, R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single
bond, Z is --CH.sub.2CH.sub.2CH.sub.2-, and R.sup.1 is ethyl or
n-propyl.
3. A compound according to claims 1 to 2, wherein R.sup.1 is a) H,
b) C.sub.1-C.sub.4 alkyl, or c) C.sub.1-C.sub.4 alkoxy
C.sub.1-C.sub.4 alkyl; R.sup.2 is a) H, b) C.sub.1-C.sub.4 alkyl,
c) halogen, d) substituted or unsubstituted carbamoyl, e)
substituted or unsubstituted carbamoyloxy, f) C.sub.1-C.sub.2
alkylcarbonyl, g) C.sub.1-C.sub.3 alkoxycarbonyl, h) cyano, i)
fluorinated C.sub.1-C.sub.2 alkoxy, j) fluorinated C.sub.1-C.sub.6
alkylthio, k) C.sub.1-C.sub.3 alkylsulfinyl, l) C.sub.1-C.sub.3
alkylsulfonyl, m) C.sub.1-C.sub.2 alkylsulfonylamino, n)
C.sub.1-C.sub.3 alkylcarbonylamino, or o) C.sub.1-C.sub.3
alkoxycarbonylamino; R.sup.3 is a) H, b) C.sub.1-C.sub.4 alkyl, or
c) halogen; R.sup.4 is a) H, b) C.sub.1-C.sub.4 alkyl, or c)
halogen; R.sup.2 and R.sup.3 may together with the carbon atoms to
which they are attached, form a saturated or unsaturated ring,
optionally containing one or more further heteroatoms, and/or
optionally substituted with one or more substituents selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OH, cyano, amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2-N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--; Any amino moiety in R.sup.2-R.sup.4 can
obtionally be substituted with one or two C.sub.1-C.sub.6 alkyl
groups which may be part of a ring; Ar is a) benzene, b) pyridine,
c) thiophene, d) pyrazine, e) pyrimidine, f) oxazole, g) thiazole,
h) pyrrole, i) pyrazole, or j) furan; X is a) --NHCO--, b)
--CONH--, c) --NH--SO.sub.2--, or d) --SO.sub.2NH--; Y is a)
--CH.sub.2--, b) --CH(C.sub.1-C.sub.6 alkyl)--, c)
--C(C.sub.1-C.sub.6 alkyl).sub.2--, or d) a single bond; Z is a)
--CH.sub.2CH.sub.2CH.sub.2--- , b)
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, c) --CH.dbd.CHCH.sub.2--, d)
--CH.dbd.CHCH.sub.2CH.sub.2--, or e) --CH.sub.2CH.dbd.CHCH.sub.2--;
excluding the racemic compounds wherein Ar is benzene,
R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single bond, Z is
--CH.sub.2CH.sub.2CH.sub.2-- -, and R.sup.1 is ethyl or
n-propyl.
4. A compound according to claims 1 to 3, wherein R.sup.1 is H;
R.sup.2 is a) H, b) C.sub.1-C.sub.4 alkyl, or c) halogen; R.sup.3
is a) H, b) C.sub.1-C.sub.4 alkyl, or c) halogen; R.sup.4 is d) H,
e) C.sub.1-C.sub.4 alkyl, or f) halogen; Ar is a) benzene, or b)
pyridine; X is a) --NHCO--, b) --CONH--, or c) --NH--SO.sub.2--; Y
is a single bond; Z is a) CH.sub.2CH.sub.2CH.sub.2--, or b)
--CH.dbd.CHCH.sub.2--; excluding the racemic compounds wherein Ar
is benzene, R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single
bond, Z is --CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or
n-propyl.
5. A compound or a pharmaceutically acceptable salt thereof,
according to claims 1 to 4 being
5-Fluorospiro[indolin-3,3'-piperidin]-2-one;
5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
(R)-5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
(S)-5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
5,7-Difluorospiro[indolin-3,3'-piperidin]-2-one acetate;
5,7-Difluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
(S)-5,7-Difluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
1',5-Dimethylspiro[indolin-3,3'-piperidin]-2-one;
5-Methyl-1'-isopropyl-s- piro[indolin-3,3'-piperidin]-2-one;
6-Methyl-1'-isopropyl-spiro[indolin-3,- 3'-piperidin]-2-one;
4-Methylspiro[indolin-3,3'-piperidin]-2-one;
4-Methyl-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one;
4-Methyl-1'-propylspiro[indolin-3,3'-piperidin]-2-one;
7-Fluorospiro[indolin-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one;
(S)-(+)-7-Fluorospiro[indolin-3,3'-piperidin]-2-one;
Spiro[indolin-3,3'-piperidin]-2-one;
1'-Ethylspiro[indolin-3,3'-piperidin- ]-2-one;
1'-Propyl-spiro[indolin-3,3'-piperidin]-2-one;
1'-Isopropylspiro[indolin-3,3'-piperidin]-2-one;
1'-Allylspiro[indolin-3,- 3'-piperidin]-2-one;
1'-Cyclopropylmethylspiro[indolin-3,3'-piperidin]-2-o- ne;
1'-Butylspiro[indolin-3,3'-piperidin]-2-one;
1'-s-Butylspiro[indolin-3- ,3'-piperidin]-2-one;
(S)-(+)-1'-Propylspiro[indolin-3,3'-piperidin]-2-one- ;
1'-Propylspiro[4-azaindolin-3,3'-piperidin]-2-one;
1'-Butylspiro[4-azaindolin-3,3'-piperidin]-2-one;
1'-sec-Butylspiro[4-aza- -indolin-3,3'-piperidin]-2-one;
1'-Propyl-5-chlorospiro[7-aza-indolin-3,3'- -piperidin]-2-one;
1'-Propylspiro[7-azaindolin-3,3'-piperidin]-2-one;
1'-Propyl-6-methylspiro[7-azaindolin-3,3'-piperidin]-2-one;
1'-Propylspiro[isoindolin-3,3'-piperidin]-1-one hydrochloride;
1'-Isopropylspiro[indoline-3,3'-piperidine]hydrochloride;
2,3-Dihydro-1H-1'-Propylspiro[thieno[3,2-b]pyrrol-3,3'-piperidin]-2-one;
2,3,1',2',3',6'-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3'-pyridin]-2-on-
e;
2,3,1',2',3',6'-Hexahydro-1H-spiro[5,8-diazaindol-3,3'-pyridin]-2-one;
1',2',3',4'-Tetrahydrospiro[indolin-3,3'-(7H)-azepin]-2-one;
1',2',3',4'-Tetrahydrospiro[7-azaindolin-3,3'-(7H)-azepin)-2-one;
1'-Ethyl-1',2',3',4'-tetrahydrospiro[4-azaindolin-3,3'-(7H)-azepin)-2-one-
;
6. A compound or a pharmaceutically acceptable salt thereof,
according to claims 1-4 being
(S)-5-Chloro-7-fluorospiro[indolin-3,3'-(1,2,3,6-tetrahy-
dropyridin)]-2-one
(S)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydr-
opyridin)]-2-one
(S)-5,6-Dimethylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahy-
dropyridin)]-2-one
(S)-6-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydr-
opyridin)]-2-one
(S)-5-Chlorospiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydrop-
yridin)]-2-one
(S)-5,7-Difluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyri-
din)]-2-one
(S)-7-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-
-one
(S)-7-Fluoro-5-methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-
-2-one
(S)-5-Methoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5-Chlorospiro[indoline-3,3'-piperidin]-2-one.
7. A compound of the formula
(S)-5-Chloro-7-fluorospiro[indolin-3,3'-(1,2,-
3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
8. A compound of the formula
(S)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-
-tetrahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
9. A compound of the formula
(S)-5,6-Dimethylspiro[7-azaindoline-3,3'-(1,2-
,3,6-tetrahydropyridin)]-2-on or a therapeutically acceptable salt
thereof.
10. A compound of the formula
(S)-6-Methylspiro[7-azaindoline-3,3'-(1,2,3,-
6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
11. A compound of the formula
(S)-5-Chlorospiro[7-azaindoline-3,3'-(1,2,3,-
6-tetrahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
12. A compound of the formula
(S)-5,7-Difluorospiro[indoline-3,3'-(1,2,3,6-
-tetrahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
13. A compound of the formula
(S)-7-Chlorospiro[indoline-3,3'-(1,2,3,6-tet-
rahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
14. A compound of the formula
(S)-7-Fluoro-5-methylspiro[indoline-3,3'-(1,-
2,3,6-tetrahydropyridin)]-2-one or a therapeutically acceptable
salt thereof.
15. A compound of the formula
(S)-5-Methoxyspiro[indoline-3,3'-(1,2,3,6-te-
trahydropyridin)]-2-one or a therapeutically acceptable salt
thereof.
16. A compound of the formula
(S)-5-Chlorospiro[indoline-3,3'-piperidin]-2- -one or a
therapeutically acceptable salt thereof.
17. A process for the preparation of a compound according to any
one of claims 1 to 16 comprising the step of A) cyclizing a
compound of the Formula VII 17wherein L is a halogen or a
trifluoromethylsulfonyl group, to give a compound of the general
Formula I using palladium as a catalyst under standard conditions;
or B) cyclizing a compound of the Formula XII 18wherein X is and X
is --NHCO--, --CONH--, --NH--SO.sub.2--, or --SO.sub.2NH--, A is
oxygen or nitrogen, and PG is a suitable protecting group, such as
Boc or benzyl when A is nitrogen and 4-methoxybenzyl when A is
oxygen, to give a compound of the general Formula I using
formaldehyde under standard Mannich conditions; or C) cyclizing a
compound of the Formula VI 19to give a compound of the general
Formula I using formaldehyde under standard Mannich conditions; or
D) cyclizing a compound of the Formula V 20wherein PG is an amino
protecting group, using a ruthenium or molybdene complex as a
catalyst under standard reaction conditions to give compounds of
the general formula I, wherein Z is CH.dbd.CHCH.sub.2--, or
--CH2CH.dbd.CHCH.sub.2--.
18. A pharmaceutical formulation containing a compound according to
any one of claims 1 to 16 as active ingredient in combination with
a pharmaceutically acceptable diluent or carrier.
19. Use of a compound according to any one of claims 1 to 16 in
therapy.
20. Use of a compound according to any one of claims 1 to 16 for
the manufacture of a medicament for the treatment of pain.
21. Use of a compound according to any of claims 1 to 16 for the
manufacture of a medicament for the treatment of neuropathic or
central pain.
22. Use of a compound according to any of claims 20 and 21 for the
manufacture of a medicament for oral use.
23. A method for treatment or prophylaxis of pain or discomfort,
comprising administering to a mammal, including man, in need of
such treatment an effective amount of a compound according to any
one of claims 1 to 16.
24. A method for treatment or prophylaxis of neuropathic or central
pain, comprising administering to a mammal, including man, in need
of such treatment an effective amount of a compound according to
any of claims 1-16.
25. A method according to any of claims 23 and 24 by oral
administration.
26. A pharmaceutical formulation for use in the treatment or
prophylaxis of pain or discomfort, comprising a compound of the
formula I according to any one of claims 1 to 16, in combination
with a pharmaceutically acceptable carrier or diluent.
27. A pharmaceutical formulation for use in the treatment or
prophylaxis of neuropathic or central pain, comprising a compound
according to any of claims 1-16, in combination with a
pharmaceutically acceptable carrier or diluent.
28. A pharmaceutical formulation according to any of claims 18, 26
and 27 for oral administration
Description
TECHNICAL FIELD
[0001] The present invention relates to novel spirooxindole
derivatives, and pharmaceutically acceptable salts thereof, with an
analgesic effect. The compounds of the invention can thus be used
in the prevention and treatment of pain. In further aspects, the
invention relates to compounds for use in therapy; to processes for
preparation of such new compounds; to pharmaceutical compositions
containing at least one compound of the invention, or a
pharmaceutically acceptable salt thereof, as active ingredient; and
to the use of the active compounds in the manufacture of
medicaments for the medical use indicated above. The invention also
relates to new intermediates for use in the preparation of the
novel compounds.
BACKGROUND ART
[0002] Certain spirooxindole derivatives are known as intermediates
in the syntheses of vasopressin receptor ligands from U.S. Pat. No.
5,728,723 (Elf Sanofi).
[0003] Patent applications WO 9741125 (SKB), WO 9711697 (MSD), WO
9527712 (CEMAF), and WO 9315051 (Elf) also discloses spirooxindoles
as synthetic intermediates.
[0004] Certain spirooxindole derivatives are known as local
anesthetics from Kornet and Thio, Journal of Medicinal Chemistry
1976, 19, 892-8. This publication discloses racemic mixtures and
biological studies were limited to toxicity (LD.sub.50) in mice and
local anesthetic activity (rat sciatic nerve blocking) in which
test the compounds were found inferior to lidocaine. No analgesic
effects of the spirooxindole derivatives are mentioned.
[0005] However, there remains a need for new therapeutic agents to
treat chronic pain. Chronic pain can be caused by injury to nerves
or by a variety of lesions. As of today there is no clear
understanding why some, more or less visible injuries may elicit
pain. Medical doctors often find even strong analgesics, such as
opioids, distressfully inefficacious when the pain state is
involving the nervous system itself, peripheral as well as central.
These pain states are often referred to as neuropathic pain. As a
final resort clinicians often prescribe drugs which are not
considered true analgesics but which by trial and error have been
found partly useful. Such agents include tricyclic antidepressants,
for example amitriptylin, anticonvulsants like carbamazepine and
gabapentin, and some local anesthetics and antiarrhythmics,
especially mexiletine.
[0006] It has surprisingly been found that certain spirooxindole
derivatives exhibit good analgesic properties and are particularly
effective in the treatment of chronic pain.
DISCLOSURE OF THE INVENTION
[0007] It has surprisingly been found that compounds of the Formula
I, which are spirooxindole derivatives, are particularly effective
analgesic compounds and thereby suitable in the treatment of
pain.
[0008] In one aspect, the present invention thus relates to
compounds of the general Formula I 2
[0009] or a pharmaceutically acceptable salt thereof, wherein
[0010] R.sup.1 is
[0011] a) H,
[0012] b) substituted or unsubstituted C.sub.1-C.sub.6 alkyl,
[0013] c) C.sub.1-C.sub.6 alkoxy C.sub.2-C.sub.6 alkyl,
[0014] d) C.sub.1-C.sub.6 alkylthio C.sub.2-C.sub.6 alkyl,
[0015] e) halogenated C.sub.1-C.sub.6 alkyl,
[0016] f) aryl C.sub.1-C.sub.6 alkyl,
[0017] g) C.sub.1-C.sub.6 alkenyl, or
[0018] h) C.sub.1-C.sub.6 cycloalkyl C.sub.1-C.sub.2 alkyl;
[0019] R.sup.2is
[0020] a) H,
[0021] b) C.sub.1-C.sub.6 alkyl,
[0022] c) C.sub.2-C.sub.4 alkynyl,
[0023] d) halogen,
[0024] e) substituted or unsubstituted carbamoyl,
[0025] f) substituted or unsubstituted carbamoyloxy,
[0026] g) C.sub.1-C.sub.6 alkylcarbonyl,
[0027] h) C.sub.1-C.sub.6 alkoxycarbonyl,
[0028] i) C.sub.1-C.sub.6 alkylcarbonyloxy,
[0029] j) hydroxy-substituted C.sub.1-C.sub.6 alkyl,
[0030] k) cyano,
[0031] l) nitro,
[0032] m) amino,
[0033] n) halogenated C.sub.1-C.sub.6 alkyl,
[0034] o) halogenated C.sub.1-C.sub.6 alkoxy,
[0035] p) halogenated C.sub.1-C.sub.6 alkylthio,
[0036] q) C.sub.1-C.sub.6 alkylsulfinyl,
[0037] r) C.sub.1-C.sub.6 alkylsulfonyl,
[0038] s) C.sub.1-C.sub.4 alkylsulfinylalkyl,
[0039] t) C.sub.1-C.sub.4 alkylsulfonylalkyl,
[0040] u) C.sub.1-C.sub.6 alkylsulfonylamino,
[0041] v) halogenated C.sub.1-C.sub.6 alkylsulfonylamino,
[0042] w) halogenated C.sub.1-C.sub.2 alkylsulfonyloxy,
[0043] x) aminosulfonyl,
[0044] y) aminosulfonyloxy,
[0045] z) aryl,
[0046] aa) heteroaryl,
[0047] bb) arylcarbonyl,
[0048] cc) heteroarylcarbonyl,
[0049] dd) arylsulfinyl,
[0050] ee) heteroarylsulfinyl,
[0051] ff) arylsulfonyl,
[0052] gg) heteroarylsulfonyl, in which any aromatic moiety is
optionally substituted,
[0053] hh) C.sub.1-C.sub.6 alkylcarbonylamino,
[0054] ii) C.sub.1-C.sub.6 alkoxycarbonylamino,
[0055] jj) C.sub.1-C.sub.6 alkyl-thiocarbonyl,
[0056] kk) C.sub.1-C.sub.6 alkoxy-thiocarbonyl,
[0057] ll) formyl, or
[0058] mm)alkoxysulfonylamino;
[0059] R.sup.3 is
[0060] a) H,
[0061] b) C.sub.1-C.sub.6 alkyl,
[0062] c) halogen,
[0063] d) C.sub.1-C.sub.6 alkoxy,
[0064] e) halogenated C.sub.1-C.sub.4 alkyl,
[0065] f) halogenated C.sub.1-C.sub.6 alkoxy,
[0066] g) halogenated C.sub.1-C.sub.6 alkylthio,
[0067] h) C.sub.1-C.sub.4 alkylsulfinyl,
[0068] i) C.sub.1-C.sub.4 alkylsulfonyl,
[0069] j) C.sub.1-C.sub.4 alkylsulfinyl C.sub.1-C.sub.6 alkyl,
[0070] k) C.sub.1-C.sub.4 alkylsulfonyl C.sub.1-C.sub.6 alkyl,
[0071] I) C.sub.1-C.sub.4 alkylsulfonylamino,
[0072] m)halogenated C.sub.1-C.sub.4 alkylsulfonylamino,
[0073] n) aminosulfonyl, or
[0074] o) aminosulfonyloxy;
[0075] R.sup.4 is
[0076] a) H,
[0077] b) C.sub.1-C.sub.4 alkyl, or
[0078] c) halogen;
[0079] R.sup.2 and R.sup.3 may together with the carbon atoms to
which they are attached, form a saturated or unsaturated ring,
optionally containing one or more further heteroatoms, and/or
optionally substituted with one or more substituents selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OH, cyano, amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2--N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--;
[0080] Any amino moiety in R.sup.2-R.sup.4 can optionally be
substituted with one or two C.sub.1 -C.sub.6 alkyl groups which may
be part of a ring;
[0081] Ar is
[0082] a) benzene,
[0083] b) pyridine,
[0084] c) thiophene,
[0085] d) pyrazine,
[0086] e) pyrimidine,
[0087] f) oxazole,
[0088] g) thiazole,
[0089] h) pyrrole,
[0090] i) pyrazole, or
[0091] j) furan;
[0092] X is
[0093] a) --NHCO--,
[0094] b) --CONH--,
[0095] c) --NH--SO.sub.2--,
[0096] d) --SO.sub.2NH--,
[0097] e) --OCH.sub.2--,
[0098] f) --NHCH.sub.2--, or
[0099] g) --NHCOCH.sub.2--;
[0100] Y is
[0101] a) --CH.sub.2--,
[0102] b) --CH(C.sub.1-C.sub.6 alkyl)--,
[0103] c) --C(C.sub.1-C.sub.6 alkyl).sub.2--, or
[0104] d) a single bond;
[0105] Z is
[0106] a) --CH.sub.2CH.sub.2CH.sub.2--,
[0107] b) --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
[0108] c) --CH.dbd.CHCH.sub.2--,
[0109] d) --CH.dbd.CHCH.sub.2CH.sub.2--, or
[0110] e) --CH.sub.2CH.dbd.CHCH.sub.2--;
[0111] provided that when X is --NHCOCH.sub.2-- then Y cannot be
--CH.sub.2--; and
[0112] excluding the racemic compounds wherein Ar is benzene,
R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single bond, Z is
--CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or n-propyl.
[0113] The pure enantiomers, racemic mixtures and unequal mixtures
of two enantiomers are within the scope of the invention. It should
be understood that also all the diastereomeric forms possible are
within the scope of the invention.
[0114] It will also be appreciated by those skilled in the art,
although derivatives of compounds of formula I may not possess
pharmacological activity as such, they may be administered
parenterally or orally and thereafter metabolized in the body to
form compounds of the invention which are pharmacologically active.
Such derivatives, of which the N-oxide is one example, may
therefore be described as "prodrugs". All prodrugs of compounds of
formula I are included within the scope of the invention.
[0115] Depending on the process conditions the final products of
the Formula I are obtained either in neutral or salt form. Salt
forms include hydrates and other solvates and also crystalline form
polymorphs. Both the free base and the salts of these end products
are within the scope of the invention.
[0116] Acid addition salts of the new compounds may in a manner
known per se be transformed into the free base using basic agents
such as alkali or by ion exchange. The free base obtained may also
form salts with organic or inorganic acids.
[0117] In the preparation of acid addition salts, preferably such
acids are used which form suitably pharmaceutically acceptable
salts. Examples of such acids are hydrochloric acid, sulfuric acid,
phosphoric acid, nitric acid, aliphatic, alicyclic carboxylic or
sulfonic acids, aromatic or heterocyclic carboxylic or sulfonic
acids, such as formic acid, acetic acid, propionic acid, succinic
acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric
acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid,
p-hydroxybenzoic acid, embonic acid, methanesulfonic acid,
ethanesulfonic acid, hydroxyethanesulfonic acid,
halogenbensenesulfonic acid, toluenesulfonic acid or
naphthalenesulfonic acid. All crystalline form polymorphs are
within the scope of the invention.
[0118] Preferred compounds of the invention are those of Formula I
wherein
[0119] R.sup.1 is
[0120] a) H,
[0121] b) C.sub.1-C.sub.4 alkyl,
[0122] c) C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl,
[0123] d) C.sub.1-C.sub.4 alkylthio C.sub.1-C.sub.4 alkyl,
[0124] e) fluorinated C.sub.1-C.sub.4 alkyl,
[0125] f) aryl C.sub.1-C.sub.4 alkyl,
[0126] g) C.sub.1-C.sub.4 alkenyl, or
[0127] h) cyclopropylmethyl;
[0128] R.sup.2 is
[0129] a) H,
[0130] b) C.sub.1-C.sub.4 alkyl,
[0131] c) C.sub.2-C.sub.3 alkynyl,
[0132] d) halogen,
[0133] e) substituted or unsubstituted carbamoyl,
[0134] f) substituted or unsubstituted carbamoyloxy,
[0135] g) C.sub.1-C.sub.3 alkylcarbonyl,
[0136] h) C.sub.1-C.sub.3 alkoxycarbonyl,
[0137] i) C.sub.1-C.sub.3 alkylcarbonyloxy,
[0138] j) hydroxy-substituted C.sub.1-C.sub.3 alkyl,
[0139] k) cyano,
[0140] l) fluorinated C.sub.1-C.sub.3 alkoxy,
[0141] m) fluorinated C.sub.1-C.sub.6 alkylthio,
[0142] n) C.sub.1-C.sub.3 alkylsulfinyl,
[0143] o) C.sub.1-C.sub.3 alkylsulfonyl,
[0144] p) C.sub.1-C.sub.3 alkylsulfinyl C.sub.1-C.sub.6 alkyl,
[0145] q) C.sub.1-C.sub.4 alkylsulfonyl C.sub.1-C.sub.6 alkyl,
[0146] r) C.sub.1-C.sub.3 alkylsulfonylamino,
[0147] s) halogenated C.sub.1-C.sub.3 alkylsulfonylamino,
[0148] t) sulfamoyl,
[0149] u) sulfamoyloxy,
[0150] v) aryl,
[0151] w) heteroaryl,
[0152] x) heteroarylsulfinyl,
[0153] y) arylsulfonyl,
[0154] z) heteroarylsulfonyl, in which any aromatic moiety is
optionally substituted,
[0155] aa) C.sub.1-C.sub.4 alkylcarbonylamino,
[0156] bb) C.sub.1-C.sub.3 alkoxycarbonylamino,
[0157] cc) C.sub.1-C.sub.3 alkyl-thiocarbonyl, or
[0158] dd) C.sub.1-C.sub.3 alkoxy-thiocarbonyl;
[0159] R.sup.3 is
[0160] a) H,
[0161] b) C.sub.1-C.sub.4 alkyl, or
[0162] c) halogen;
[0163] R.sup.4 is
[0164] a) H,
[0165] b) C.sub.1-C.sub.4 alkyl, or
[0166] c) halogen,
[0167] R.sup.2 and R.sup.3 may together with the carbon atoms to
which they are attached, form a saturated or unsaturated ring,
optionally containing one or more further heteroatoms, and/or
optionally substituted with one or more substituents selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OH, cyano, amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2--N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--;
[0168] Any amino moiety in R.sup.2-R.sup.4 can obtionally be
substituted with one or two C.sub.1-C.sub.6 alkyl groups which may
be part of a ring;
[0169] Ar is
[0170] a) benzene,
[0171] b) pyridine,
[0172] c) thiophene,
[0173] d) pyrazine,
[0174] e) pyrimidine,
[0175] f) oxazole,
[0176] g) thiazole,
[0177] h) pyrrole,
[0178] i) pyrazole, or
[0179] j) furan;
[0180] X is
[0181] a) --NHCO--,
[0182] b) --CONH--,
[0183] c) --NH--SO.sub.2--, or
[0184] d) --SO.sub.2NH--;
[0185] Y is
[0186] a) --CH.sub.2--,
[0187] b) --CH(C.sub.1-C.sub.6 alkyl)-,
[0188] c) --C(C.sub.1-C.sub.6 alkyl).sub.2-- or
[0189] d) a single bond;
[0190] Z is
[0191] a) --CH.sub.2CH.sub.2CH.sub.2--,
[0192] b) --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
[0193] c) --CH.dbd.CHCH.sub.2--,
[0194] d) --CH.dbd.CHCH.sub.2CH.sub.2--, or
[0195] e) --CH.sub.2CH.dbd.CHCH.sub.2--;
[0196] provided that when X is --NHCOCH.sub.2-- then Y cannot be
--CH.sub.2--; and
[0197] excluding the racemic compounds wherein Ar is benzene,
R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single bond, Z is
--CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or n-propyl.
[0198] More preferred compounds of the invention are those of
Formula I wherein
[0199] R.sup.1 is
[0200] a) H,
[0201] b) C.sub.1-C.sub.4 alkyl, or
[0202] c) C.sub.1-C.sub.4 alkoxy C.sub.1-C.sub.4 alkyl;
[0203] R.sup.2 is
[0204] a) H,
[0205] b) C.sub.1-C.sub.4 alkyl,
[0206] c) halogen,
[0207] d) substituted or unsubstituted carbamoyl,
[0208] e) substituted or unsubstituted carbamoyloxy,
[0209] f) C.sub.1-C.sub.2 alkylcarbonyl,
[0210] g) C.sub.1-C.sub.3 alkoxycarbonyl,
[0211] h) cyano,
[0212] i) fluorinated C.sub.1-C.sub.2 alkoxy,
[0213] j) fluorinated C.sub.1-C.sub.6 alkylthio,
[0214] k) C.sub.1-C.sub.3 alkylsulfinyl,
[0215] l) C.sub.1-C.sub.3 alkylsulfonyl,
[0216] m) C.sub.1-C.sub.2 alkylsulfonylamino,
[0217] n) C.sub.1-C.sub.3 alkylcarbonylamino, or
[0218] o) C.sub.1-C.sub.3 alkoxycarbonylamino;
[0219] R.sup.3 is
[0220] a) H,
[0221] b) C.sub.1-C.sub.4 alkyl, or
[0222] c) halogen;
[0223] R.sup.4 is
[0224] a) H,
[0225] b) C.sub.1-C.sub.4 alkyl, or
[0226] c) halogen;
[0227] R.sup.2 and R.sup.3 may together with the carbon atoms to
which they are attached, form a saturated or unsaturated ring,
optionally containing one or more further heteroatoms, and/or
optionally substituted with one or more substituents selected from
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, CF.sub.3,
OH, cyano, amino, C.sub.1-C.sub.6 alkyl-NH--, (C.sub.1-C.sub.6
alkyl).sub.2-N--, CN, NH.sub.2SO.sub.2, NH.sub.2CO--, or
C.sub.1-C.sub.6 alkyl-CO--;
[0228] Any amino moiety in R.sup.2-R.sup.4 can optionally be
substituted with one or two C.sub.1-C.sub.6 alkyl groups which may
be part of a ring;
[0229] Ar is
[0230] a) benzene,
[0231] b) pyridine,
[0232] c) thiophene,
[0233] d) pyrazine,
[0234] e) pyrimidine,
[0235] f) oxazole,
[0236] g) thiazole,
[0237] h) pyrrole,
[0238] i) pyrazole, or
[0239] j) furan;
[0240] X is
[0241] a) --NHCO--,
[0242] b) --CONH--,
[0243] c) --NH--SO.sub.2--, or
[0244] d) --SO.sub.2NH--;
[0245] Y is
[0246] a) --CH.sub.2--,
[0247] b) --CH(C.sub.1-C.sub.6 alkyl)-,
[0248] c) --C(C.sub.1-C.sub.6 alkyl).sub.2-, or
[0249] d) a single bond;
[0250] Z is
[0251] a) --CH.sub.2CH.sub.2CH.sub.2--,
[0252] b) --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
[0253] c) --CH.dbd.CHCH.sub.2--,
[0254] d) --CH.dbd.CHCH.sub.2CH.sub.2--, or
[0255] e) --CH.sub.2CH.dbd.CHCH.sub.2--;
[0256] excluding the racemic compounds wherein Ar is benzene,
R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single bond, Z is
--CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or n-propyl.
[0257] Particularly preferred compounds of the invention are those
of Formula I wherein
[0258] R.sup.1 is H;
[0259] R.sup.2 is
[0260] a) H,
[0261] b) C.sub.1-C.sub.4 alkyl, or
[0262] c) halogen;
[0263] R.sup.3 is
[0264] a) H,
[0265] b) C.sub.1-C.sub.4 alkyl, or
[0266] c) halogen;
[0267] R.sup.4 is
[0268] a) H,
[0269] b) C.sub.1-C.sub.4 alkyl, or
[0270] c) halogen;
[0271] Ar is
[0272] a) benzene, or
[0273] b) pyridine;
[0274] X is
[0275] a) --NHCO--,
[0276] b) --CONH--, or
[0277] c) --NH--SO.sub.2--;
[0278] Y is a single bond;
[0279] Z is
[0280] a) CH.sub.2CH.sub.2CH.sub.2--, or
[0281] b) --CH.dbd.CHCH.sub.2--,
[0282] excluding the racemic compounds wherein Ar is benzene,
R.sup.2-R.sup.4 is hydrogen, X is NHCO, Y is a single bond, Z is
--CH.sub.2CH.sub.2CH.sub.2--, and R.sup.1 is ethyl or n-propyl.
[0283] It has furthermore surprisingly been found that the
(S)-enantiomers of the compounds of formula I possess a higher
analgesic activity than the (R)-enantiomers and are thus preferred
for therapeutic use before the latter and the racemic mixtures.
[0284] Another aspect of the present invention is therefore the
S-enantiomer, referring to the marked spirocarbon, of the compounds
of the general Formula I 3
[0285] or a pharmaceutically acceptable salt thereof, as defined
above.
[0286] The following definitions shall apply throughout the
specification and the appended claims:
[0287] The term "C.sub.1-C.sub.6 alkyl" denotes a cyclic or linear,
straight or branched, substituted or unsubstituted alkyl group
having from 1 to 6 carbon atoms. Examples of said alkyl include,
but is not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, cyclohexyl, and cyclopentyl.
[0288] The term "C.sub.1-C.sub.6 alkoxy" denotes a group O-alkyl,
wherein alkyl is as defined above.
[0289] The terms "C.sub.1-C.sub.4 alkyl", "C.sub.1-C.sub.3 alkyl",
"C.sub.1-C.sub.2 alkyl" have the corresponding meaning as
"C.sub.1-C.sub.6 alkyl".
[0290] The term "halogen" includes fluoro, chloro, bromo and iodo
groups.
[0291] The term "aryl" denotes a substituted or unsubstituted
C.sub.6-C.sub.14 aromatic hydrocarbon and includes, but is not
limited to, benzene, naphtalene, indene, antracene, fenantrene, and
fluorene.
[0292] The term "substituted" denotes e.g. an Cl-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylaryl or aryl group as defined above which is
substituted by one or more alkyl, alkoxy, halogen, amino, thiol,
nitro, hydroxy, acyl, cyano or oxo groups.
[0293] The term "heteroatoms" denotes a nitrogen, oxygen, sulfur,
or a phosphorous atom.
[0294] Most preferred compounds according to the invention are
listed in the following table. The compounds can be in neutral form
or in salt form as earlier indicated, for example in hydrochloride
form.
[0295] 5-Fluorospiro[indolin-3,3'-piperidin]-2-one
[0296] 5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0297]
(R)-5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0298]
(S)-5-Fluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0299] 5,7-Difluorospiro[indolin-3,3'-piperidin]-2-one acetate
[0300]
5,7-Difluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0301]
(S)-5,7-Difluoro-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0302] 1',5-Dimethylspiro[indolin-3,3'-piperidin]-2-one
[0303]
5-Methyl-1'-isopropyl-spiro[indolin-3,3'-piperidin]-2-one
[0304]
6-Methyl-1'-isopropyl-spiro[indolin-3,3'-piperidin]-2-one
[0305] 4-Methylspiro[indolin-3,3'-piperidin]-2-one
[0306] 4-Methyl-1'-isopropylspiro[indolin-3,3'-piperidin]-2-one
[0307] 4-Methyl-1'-propylspiro[indolin-3,3'-piperidin]-2-one
[0308]
7-Fluorospiro[indolin-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
[0309] (S)-(+)-7-Fluorospiro[indolin-3,3'-piperidin]-2-one
[0310] Spiro[indolin-3,3'-piperidin]-2-one
[0311] 1'-Ethylspiro[indolin-3,3'-piperidin]-2-one
[0312] 1'-Propyl-spiro[indolin-3,3'-piperidin]-2-one
[0313] 1'-Isopropylspiro[indolin-3,3'-piperidin]-2-one
[0314] 1'-Allylspiro[indolin-3,3'-piperidin]-2-one
[0315] 1'-Cyclopropylmethylspiro[indolin-3,3'-piperidin]-2-one
[0316] 1'-Butylspiro[indolin-3,3'-piperidin]-2-one
[0317] 1'-s-Butylspiro[indolin-3,3'-piperidin]-2-one
[0318] (S)-(+)-1'-Propylspiro[indolin-3,3'-piperidin]-2-one
[0319] 1'-Propylspiro[4-azaindolin-3,3'-piperidin]-2-one
[0320] 1'-Butylspiro[4-azaindolin-3,3'-piperidin]-2-one
[0321] 1'-sec-Butylspiro[4-aza-indolin-3,3'-piperidin]-2-one
[0322]
1'-Propyl-5-chlorospiro[7-aza-indolin-3,3'-piperidin]-2-one
[0323] 1'-Propylspiro[7-azaindolin-3,3'-piperidin]-2-one
[0324]
1'-Propyl-6-methylspiro[7-azaindolin-3,3'-piperidin]-2-one
[0325] 1'-Propylspiro[isoindolin-3,3'-piperidin]-1-one
hydrochloride
[0326] 1'-Isopropylspiro[indoline-3,3'-piperidine]hydrochloride
[0327]
2,3-Dihydro-1H-1'-Propylspiro[thieno[3,2-b]pyrrol-3,3'-piperidin]-2-
-one
[0328]
2,3,1',2',3',6'-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3'-pyridin-
]-2-one
[0329]
2,3,1',2',3',6'-Hexahydro-1H-spiro[5,8-diazaindol-3,3'-pyridin]-2-o-
ne
[0330]
1',2',3'4'-Tetrahydrospiro[indolin-3,3'-(7H)-azepin]-2-one
[0331]
1',2',3'4'-Tetrahydrospiro[7-azaindolin-3,3'-(7H)-azepin)-2-one
[0332]
1'-Ethyl-1',2',3'4'-tetrahydrospiro[4-azaindolin-3,3'-(7H)-azepin)--
2-one
[0333] 1'-Propylspiro[indolin-3,3'-piperidin]-2-one 1'-oxide
[0334] Further most preferred compounds according to the
invention:
[0335] Also these compounds can be in neutral form or in salt form
as earlier indicated.
[0336]
(S)-5-Chloro-7-fluorospiro[indolin-3,3'-(1,2,3,6-tetrahydropyridin)-
]-2-one
[0337]
(S)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-
-one
[0338]
(S)-5,6-Dimethylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin-
)]-2-one
[0339]
(S)-6-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-
-one
[0340]
(S)-5-Chlorospiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-
-one
[0341]
(S)-5,7-Difluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2--
one
[0342]
(S)-7-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
[0343]
(S)-7-Fluoro-5-methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin-
)]-2-one
[0344]
(S)-5-Methoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
[0345] (S)-5-Chlorospiro[indoline-3,3'-piperidin]-2-one
Preparation
[0346] The present invention also provides the following processes
for the preparation of compounds of the general Formula I. The
compounds of the present invention can be prepared by methods known
in the art using commercially available, or readily prepared,
starting materials. Many useful methods for synthesis of oxindoles
are reviewed by G. M. Karp in Org. Prep. Proced. Int. 1993, 25,
481-513, which is incorporated herein by reference.
[0347] It is to be understood that certain functional groups may
interfere with other reactants or reagents under the reaction
conditions and therefore may need temporary protection. The use of
protecting groups is described in `Protective Groups in Organic
Synthesis`, 2nd edition, T. W. Greene & P. G. M. Wutz,
Wiley-Interscience (1991).
[0348] Process A
[0349] A process for manufacture of compounds with the general
Formula I comprises the following steps:
[0350] a) Compounds of Formula IV 4
[0351] wherein L is a halogen or a trifluoromethylsulfonyloxy
group, Ar, R.sup.2-R.sup.4 are as defined in Formula I, or can be
converted into such groups later in the synthesis sequence, is
coupled with a compound of the general Formula II, or a
corresponding lower alkyl ester, e.g. methyl or ethyl ester, 5
[0352] wherein R.sup.1 is as defined for Formula I or is a nitrogen
protecting group, e.g. a Boc group, to give a compound of the
general Formula VII 6
[0353] b) The resulting amide of the general Formula VII is then
cyclized using Heck reaction conditions with palladium as a
catalyst or sometimes under radical generating conditions to give,
after optional removal of protecting groups, a compound of the
general formula I
[0354] When the above formed spiro compound contains a double bond
this may be hydrogenated over a metal catalyst to give the
corresponding saturated compound, or by other methods well known to
those skilled in the art. The product is thereafter deprotected, if
necessary, or the cyclized protected intermediate compound may be
further reacted with, for example organometallic reagents, to give
new compounds of the invention in which an alkyl or alkynyl group
is substituted for a bromine or an aryl- or alkylsulfonyloxy
group.
[0355] Process B
[0356] a) Compounds of Formula IV 7
[0357] wherein Ar, R.sup.2-R.sup.4, Y are as defined in Formula I,
and X is --NHCO-- or --NH--SO.sub.2 are alkylated with a compound
of the general Formula IX 8
[0358] wherein Z is as defined in Formula I, L is a bromine,
iodine, aryl or alkylsulfonyloxy group, e.g.
trifluoromethylsulfonyloxy group, A is oxygen or nitrogen, and PG
is a suitable protecting group or, when A is nitrogen, equals
R.sup.1 of Formula I, to give compounds of the general formula XII
9
[0359] wherein Ar, R.sup.2-R.sup.4, and Z are as defined in Formula
I, X is --NHCO--, or --NH--SO.sub.2--, A is oxygen or nitrogen and
PG is a suitable protecting group or, when A is nitrogen, equals
R.sup.1 of Formula I.
[0360] b) An optional transformation step is performed when A is
oxygen, wherein the oxygen function is converted into the
corresponding amino function by methods well known in the art. One
suitable way of accomplishing this conversion is to remove the
protecting group to generate the corresponding primary alcohol,
which is thereafter converted into a suitable leaving groups, e.g.
a tosylate group. The leaving group is thereafter displaced by a
suitable amino nucleophile to give a compound of the general
formula XII, wherein A is nitrogen.
[0361] c) Compounds of the general formula XII can thereafter and
after optional removal of protecting groups be cyclized to the
spiro system to give compounds of the formula I under standard
Mannich conditions.
[0362] Process C
[0363] a) Compounds of the general Formula III 10
[0364] wherein Ar, R.sup.1-R.sup.4 are as defined in Formula I or
R.sup.1 is a benzylic protecting group, are oxidised into compounds
of the general Formula VI, 11
[0365] wherein Ar, R.sup.1-R.sup.4 are as defined in Formula I or
R.sup.1 is a benzylic protecting group, as is described in Kornet
and Thio, Journal of Medicinal Chemistry 1976, 19, 892-8 or as
referred to in the previously mentioned review by Karp.
[0366] c) Compounds of the general Formula VI are thereafter
cyclized under standard Mannich reaction conditions to give a
compound of the general Formula I.
[0367] Process D
[0368] a) Compounds of the general Formula V 12
[0369] wherein Ar, R.sup.2-R.sup.4, X and Y are as defined in
Formula I and PG is an amino protecting group, is ring-closed using
a ruthenium or molybdene complex as a catalyst under standard
reaction conditions to give compounds of the general formula VIII
13
[0370] This metathesis reaction is described in more detail in the
review by Grubbs, R. H. and Chang, S. Tetrahedron 1998, 54,
4413-50.
[0371] The intermediate V may be prepared by methods known to the
one skilled in the art, for example by alkylation of the
intermediate IV with e.g. allyl bromide followed by a Mannich
reaction with a secondary amine to give a compound of the general
formula Va, as is schematically shown below. 14
[0372] In process B and C the amino protecting group used is
preferably an easily removable group, for example groups belonging
to the arylmethyl class which can be readily removed by
hydrogenolysis, thus releasing the secondary amine of formula I
(R.sup.1.dbd.H). Said compound can be converted to a tertiary
amine, by alkylating methods well known in the art. Other suitable
protective groups that are described in the organic chemical
literature is, for example, an allyl carbamate or a 4-methoxybenzyl
group.
[0373] Many interconversions of the R.sup.2 and R.sup.3 groups are
also evident to one skilled in the art.
[0374] Compounds of the general formula I prepared in this way are
racemic. As is well known in the art resolution of the two
enantiomers can be conveniently achieved by classical
crystallization methods by using a chiral acid such as L- or
D-ditoluoyltartaric acid or (+) or (-)-1-camphorsulfonic acid in a
suitable solvent such as acetone, water, alcohol, ethyl acetate or
their mixture. Another method to achieve the same goal is to
separate the enantiomers by chromatography on a chiral column such
as Chiralcel OD or Kromasil TBB which are commercially available. A
further well known means to obtain pure enantiomers is by preparing
a derivative of a racemic intermediate, for example an amide of a
secondary amine, with an enantiomerically pure acid and then
separating the so formed diastereomers by crystallization or by
chromatography.
Medical Use
[0375] In a further aspect, the present invention relates to
compounds of the formula I for use in therapy, in particular for
use in the treatment of pain. The invention also provides the use
of a compound of the formula I in the manufacture of a medicament
for the treatment of pain.
[0376] The novel compounds of the present invention are useful in
therapy, especially for the treatment and/or prophylaxis of pain of
widely different origins and causes and include acute as well as
chronic pain states. Examples are pain caused by chemical,
mechanical, radiation, thermal, infectious or inflammatory tissue
trauma or cancer, postoperative pain, headache and migraine,
various arthritic and inflammatory conditions such as osteo and
rheumatoid arthritis, myofascial and low back pain.
[0377] Also neuropathic conditions of central or peripheral origin
can be treated or prevented with the compounds of the invention.
Examples of these pain conditions are trigeminal neuralgia,
postherpetic neuralgia (PHN), diabetic mono/poly neuropathy, nerve
trauma, spinal cord injury, central post stroke, multiple sclerosis
and Parkinson's disease. Other pain states of visceral origin such
as caused by ulcer, dysmenorrhea, endometriosis, IBS, dyspepsia
etc. can also be treated or prevented with the compounds of the
invention. The compounds of the invention are useful as therapeutic
agents in disease states with inappropriate neuronal activity or in
neuroprotection for example as anticonvulsants in epilepsy, in the
treatment of itch, tinnitus, Parkinson's disease, multiple
sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer, stroke,
cerebral ischaemia, traumatic brain injury, Huntingdon's chorea,
schizophrenia, obsessive compulsive disorders (OCD), neurological
deficits associated with AIDS, sleep disorders (including circadian
rhythm disorders, insomnia & narcolepsy), tics (e.g. Tourette's
syndrome), and muscular rigidity (spasticity).
[0378] A primary aim of the invention is to use compounds of the
formula I for oral treatment of neuropathic or central pain
states.
[0379] The compounds of the invention are also useful for treatment
of effects associated with withdrawal from substances of abuse such
as cocaine, nicotine, alcohol and benzodiazepines.
[0380] In a further aspect the invention provides the use of a
compound of formula I, or a pharmaceutically acceptable salt or
solvate, thereof as a therapeutic agent, in particular for the
treatment and/or prophylaxis of anxiety, mania, depression, panic
disorders and/or aggression.
[0381] The typical daily dose of the active substance varies within
a wide range and will depend on various factors such as for example
the individual requirement of each patient, the route of
administration and the disease. In general, the dosages will be in
the range of 0.1 to 1000 mg per day of active substance.
Pharmaceutical Formulations
[0382] In yet a further aspect, the invention relates to
pharmaceutical compositions containing at least one compound of the
present invention, or a pharmaceutically acceptable salt thereof,
as active ingredient.
[0383] For clinical use, the compounds of the invention are
formulated into pharmaceutical formulations for oral, intravenous,
subcutaneous, tracheal, bronchial, intranasal, pulmonary,
transdermal, buccal, rectal, parenteral or other mode of
administration. The pharmaceutical formulation contains a compound
of the invention in combination with one or more pharmaceutically
acceptable ingredients. The carrier may be in the form of a solid,
semi-solid or liquid diluent, or a capsule. These pharmaceutical
preparations are a further object of the invention. Usually the
amount of active compounds is between 0.1-95% by weight of the
preparation.
[0384] In the preparation of pharmaceutical formulations containing
a compound of the present invention the compound selected may be
mixed with solid, powdered ingredients, such as lactose,
saccharose, sorbitol, mannitol, starch, amylopectin, cellulose
derivatives, gelatin, or another suitable ingredient, as well as
with disintegrating agents and lubricating agents such as magnesium
stearate, calcium stearate, sodium stearyl fumarate and
polyethylene glycol waxes. The mixture may then be processed into
granules or pressed into tablets.
[0385] Soft gelatine capsules may be prepared with capsules
containing a mixture of the active compound or compounds of the
invention, vegetable oil, fat, or other suitable vehicle for soft
gelatine capsules. Hard gelatine capsules may contain granules of
the active compound. Hard gelatine capsules may also contain the
active compound in combination with solid powdered ingredients such
as lactose, saccharose, sorbitol, mannitol, potato starch,
cornstarch, amylopectin, cellulose derivatives or gelatine.
[0386] Dosage units for rectal administration may be prepared (i)
in the form of suppositories which contain the active substance
mixed with a neutral fat base; (ii) in the form of a gelatine
rectal capsule which contains the active substance in a mixture
with a vegetable oil, paraffin oil or other suitable vehicle for
gelatine rectal capsules; (iii) in the form of a ready-made micro
enema; or (iv) in the form of a dry micro enema formulation to be
reconstituted in a suitable solvent just prior to
administration.
[0387] Liquid preparations may be prepared in the form of syrups or
suspensions, e.g. solutions or suspensions containing the active
ingredient and the remainder consisting, for example, of sugar or
sugar alcohols and a mixture of ethanol, water, glycerol, propylene
glycol and polyethylene glycol. If desired, such liquid
preparations may contain coloring agents, flavouring agents,
preservatives, saccharine and carboxymethyl cellulose or other
thickening agents. Liquid preparations may also be prepared in the
form of a dry powder to be reconstituted with a suitable solvent
prior to use.
[0388] Solutions for parenteral administration may be prepared as a
solution of a compound of the invention in a pharmaceutically
acceptable solvent. These solutions may also contain stabilizing
ingredients, preservatives and/or buffering ingredients. Solutions
for parenteral administration may also be prepared as a dry
preparation to be reconstituted with a suitable solvent before
use.
[0389] The typical daily dose of the active substance varies within
a wide range and will depend on various factors such as for example
the individual requirement of each patient, the route of
administration and the disease. In general, oral and parenteral
dosages will be in the range of 0.1 to 1000 mg per day of active
substance.
[0390] The compounds according to the present invention can also be
used in formulations, together or in combination for simultaneous,
separate or sequential use, with other active ingredients, such
as
[0391] a) opioid analgesics, for example morphine, ketobemidone or
fentanyl
[0392] b) analgesics of the NSAID class, for example ibuprofene,
selecoxib or acetylsalicylic acid
[0393] c) amino acids such as gabapentin or pregabalin
[0394] d) analgesic adjuvants such as amitriptyline or
mexiletine
[0395] e) NMDA antagonists for example ketamine or
dextrometorfan
[0396] f) sodium channel blocking agents for example lidocaine
[0397] g) anticonvulsants, for example carbamazepine or
lamotrigine
[0398] h) cannabinoids
Intermediates
[0399] A further aspect of the invention is new intermediate
compounds which are useful in the synthesis of compounds according
to the invention.
[0400] Thus, the invention includes
[0401] (a) a compound of the formula XI 15
[0402] wherein Ar, R.sup.1-R.sup.4 and X are as defined for Formula
I, L is bromide, iodide, or triflate and R.sup.1 may also be a
nitrogen protecting group, such as a alkoxycarbonyl or a benzyl
group, of which t-butoxycarbonyl is especially preferred and X,
when containing a nitrogen atom, may optionally be substituted with
a t-butoxycarbonyl group.
EXAMPLES
1. Preparation of Compounds of the Invention
[0403] All chemicals and reagents were used as received from
suppliers. .sup.13C and .sup.1H nuclear magnetic resonance (NMR)
spectra were recorded on a Varian Unity 400 (400 MHz) spectrometer.
Silica gel chromatography (SGC) was carried out on silica gel 60
(230-400 mesh). Mass spectrometry (MS) was carried out in the
positive thermospray (TSP+), chemical ionization (CI), or in the
electron impact (EI) modes.
[0404] Other abbreviations: Boc, t-butyloxycarbonyl; DCM,
dichloromethane; EtOAc ethyl acetate.
Example 1
5-Fluorospiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0405] STEP A. t-Butyl
3-(2-bromo-4-fluorophenylcarbamoyl)-1,2,5,6-tetrahy-
dropyridine-1-carboxylate. 2-Bromo-4-fluoroaniline (2.53 g, 13.3
mmol) was dissolved in dichloromethane (30 mL) under
N.sub.2-atmosphere and trimethylaluminium (2.0 M in hexanes, 8 mL)
was added. The solution was stirred during 15 minutes, whereupon a
solution of 5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-t-butyl
ester 3-methyl ester (3.67 g, 13.3 mmol) in DCM (20 mL) was added.
The mixture was refluxed overnight and saturated NaHCO.sub.3 was
carefully added followed by DCM. The aqueous phase was extracted
with DCM. The crude product was purified by chromatography on
silica gel using a gradient of toluene to acetonitrile to give the
title compound (4.55 g) in 86 % yield as an yellow oil. R.sub.f
0.54 (toluene/acetonitrile 3:1). MS(TSP+) m/z calcd for
[M+NH.sub.4].sup.+: 416, 418, observed: 416, 418.
[0406] STEP B. t-Butyl
3-[(2-bromo-4-fluorophenyl)-(t-butoxycarbonyl)-carb-
amoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. The product from
STEP A (3.51 g) was dissolved in dry acetonitrile under
N.sub.2-atmosphere. 4-Dimethylaminopyridine (120 mg, 0.98 mmol) and
di-t-butyl dicarbonate (2.08 g, 9.53 mmol) were added. After
reaction overnight the acetonitrile was stripped off and the
residue was dissolved in diethyl ether (200 mL). The ethereal phase
was extracted with 0.2 M aqueous solution of citric acid
(3.times.50 mL) and then with saturated NaHCO.sub.3 (3.times.50
mL). The product was purified by chromatography on silica gel using
a gradient of toluene to acetonitrile to give the title compound in
91% yield as a yellow oil. MS(TSP+) m/z observed: 516, 518
(20%).
[0407] STEP C.
Di-t-butyl5-fluoro-2-oxospiro[indoline-3,3'-(1,2,3,6-tetrah-
ydropyridin)]-1,1'-dicarboxylate. The amide from STEP B (994 mg,
1.99 mmol) was dissolved in acetonitrile (20 mL) under
N.sub.2-atmosphere. Triphenylphosphine (133 mg, 0.51 mmol),
triethylamine (0.42 mL, 3 mmol) and palladium acetate (50 mg, 0.22
mmol) were added. The mixture was refluxed for 5 days under
N.sub.2-atmosphere. The crude product was purified by
chromatography on silica gel and eluted with a gradient of toluene
to acetonitrile to give the title compound (604 mg) in 73% yield as
a yellow oil. R.sub.f 0.58 (toluene/acetonitrile 3:1). MS(CI,
NH.sub.3) m/z 436.
[0408] STEP D. t-Butyl
5-fluoro-2-oxospiro[indoline-3,3'-(1,2,3,6-tetrahyd-
ro-pyridin)]-1'-carboxylate. The compound from STEP A (1.00 g, 2.50
mmol) was cyclised to the title compound (382 mg) in 48% yield
following the same procedure as described in STEP C. MS (TSP+) m/z
[M+H].sup.+: 319.
[0409] STEP E. Di-t-butyl
5-fluoro-2-oxospiro[indoline-3,3'-piperidin]-1,1- '-dicarboxylate.
The product from STEP C (590 mg, 1.41 mmol) was hydrogenated in
absolute ethanol (20 mL) using PtO.sub.2 and H.sub.2 (3.5 atm) for
2 days. The reaction mixture was filtered using 00H-filter paper
and the solvent was evaporated to give the title compound (563 mg)
in 95% yield. MS (TSP+) m/z calcd for [M-BOC+H].sup.+: 321,
observed: 321.
[0410] STEP F. t-Butyl
5-fluoro-2-oxospiro[indoline-3,3'-piperidin]-1'-car- boxylate. The
product from STEP D (344 mg, 1.08 mmol) was transformed to the
title compound (295 mg) following the same procedure as described
in STEP E. MS (TSP+) m/z [M+H].sup.+: 321.
[0411] STEP G. 5-Fluorospiro[indoline-3,3'-piperidin]-2-one
hydrochloride. The product from STEP E. (563 mg, 1.34 mmol) was
dissolved in methanol (10 mL) and was treated with HCI (2.5 M
ethereal solution, 5 mL). The solvents were stripped off to give
the product (341 mg) in 99% yield as a white solid. The same
procedure was also applied to the product from STEP F. MS(TSP+) m/z
calcd for [M-Cl].sup.+: 221, observed: 221.
Example 2
5-Fluoro-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0412] The amine from EXAMPLE 1 was alkylated using PROCEDURE 1,
Method A. The crude product was purified by chromatography on
silica gel using a gradient of toluene to acetonitrile/triethyl
amine 100:5 to give the amine in 64% yield. .sup.13C-NMR
(CDCl.sub.3) .delta. 182.3, 158.5 (d, J236 Hz), 136.4, 135.9, 114.4
(d, J26 Hz), 113.4 (d, J25 Hz), 109.8, 54.8, 53.9, 49.2, 48.9,
32.0, 21.7, 18.0, 17.6. It was converted to the title compound with
HCl in ether. MS(TSP+) m/z calcd for [M-Cl].sup.+: 263, observed:
263.
Example 3
(R)-5-Fluoro-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride.
[0413] 5-Fluoro-1'-isopropyl-spiro[indoline-3,3'-piperidin]-2-one
(215 mg) from EXAMPLE 2 was chromatographed on a Kromasil TBB
column eluting with hexane/1-propanol/1-butanol 99:0.5:0.5. The
pure stereoisomer (72 mg) was collected as the first eluting peak
in 67% yield and an enantiomeric excess of 97%.
[.alpha.].sub.589.sup.22-1.18.degree.,
[.alpha.].sub.365.sup.22-10.0.degree. (c 1.01, CHCl.sub.3). It was
converted to the title compound.
[.alpha.].sub.589.sup.22-6.93.degree. (c 1.01, MeOH).
Example 4
(S)-5-Fluoro-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one.
[0414] 62 mg was collected from EXAMPLE 3 as the second enantiomer
in 58% yield and an enantiomeric excess of 99%.
[.alpha.].sub.589.sup.22+1.05.de- gree.,
[.alpha.].sub.365.sup.22+9.32.degree. (c 1.03, CHCl.sub.3). It was
converted to the hydrochloride.
[.alpha.].sub.589.sup.22+6.22.degree., (c 1.03, MeOH).
Example 5
5,7-Difluorospiro[indoline-3,3'-piperidin]-2-one acetate
[0415] STEP A. 1
-Benzyl-N-(2-bromo-4,6-difluorophenyl)-1,2,5,6-tetrahydro-
pyridine-3-carboxamide. The title compound was prepared from
2-bromo-4,6-difluoroaniline and
1-benzyl-1,2,5,6-tetrahydropyridine-3-car- boxylic acid methyl
ester as described in EXAMPLE 1. R.sub.f 0.53
(toluene/acetonitrile/tri-ethyl amine 10:10:1).
[0416] STEP B.
5,7-Difluoro-1'-benzylspiro[indoline-3,3'-(1,2,3,6-tetrahyd-
ropyridin)]-2-one.
[0417] The product from STEP A was cyclized as described in EXAMPLE
1.
[0418] STEP C. 5,7-Difluorospiro[indoline-3,3'-piperidin]-2-one
acetate. The product from STEP B was hydrogenated in glacial acetic
acid (20 mL) using 10% Pd/C and H.sub.2 (3.5 atm) for 24 hours. The
title compound was obtained in 86% yield as a crystalline solid.
MS(TSP+) m/z calcd for [M-AcO].sup.+: 239, observed: 239.
Example 6
5,7-Difluoro-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0419] The amine from the previous EXAMPLE was alkylated as
described in EXAMPLE 2 to give the free amine of the title compound
in 58% yield as a white solid. .sup.13C-NMR (CDCl.sub.3) .delta.
180.3, 157.9 (d, J240 Hz), 146.0 (d, J244 Hz), 137.8, 123.2 (d, J11
Hz), 110.3 (d, J25 Hz), 102.6 (dd, J21, 21 Hz), 54.9, 53.9, 49.4,
48.7, 32.1, 21.6, 18.1, 17.6. It was converted to the
hydrochloride. MS(TSP+) m/z calcd for [M-Cl].sup.+: 281, observed:
281.
EXAMPLE 7
(S)-5,7-Difluoro-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0420] STEP A. Chromatography.
5,7-Difluoro-1'-isopropyl-spiro[indoline-3,- 3'-piperidin]-2-one
(231 mg) from the preceding example was chromatographed on a
Kromasil TBB column eluting with hexane/1-propanol/1-butanol
98:1:1. (R)-5,7-Difluoro-1'-isopropylspiro[in-
doline-3,3'-piperidin]-2-one (94 mg) was collected as the first
enantiomer in 81% yield and an enantiomeric excess of 97.6%.
-0.30.degree. (c 1.00, CHCl.sub.3).
(S)-5,7-Difluoro-1'-isopropyl-spiro[indoline-3,3'-piperidin]-
-2-one was collected as the second peak (92 mg) in 80% yield and an
enantiomeric excess of 98.4%, +0.12.degree. (c 1.00,
CHCl.sub.3).
[0421] STEP B.
(S)-5,7-Difluoro-1'-isopropylspiro[indoline-3,3'-piperidin]- -2-one
hydrochloride. The (S)-enantiomer from STEP A was converted to the
hydrochloride to give the title compound as a white solid,
6.20.degree. (c 1.00, MeOH).
Example 8
1',5-Dimethylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride.
[0422] The title compound was prepared from
2-Bromo-4-methyl-aniline and arecholine hydrobromide as described
in EXAMPLE 1. MS(TSP+) m/z calcd for [M-Cl].sup.+: 231, observed:
231
Example 9
5-Methyl-1'-isopropyl-spiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0423] The title compound was obtained from 2-bromo-4
methyl-aniline and methyl
N-benzyl-1,2,3,6-tetrahydropyridin-3-carboxylate as described in
EXAMPLE 1. MS(TSP+) m/z calcd for [M-Cl].sup.+: 259, observed:
259.
Example 10
6-Methyl-1'-isopropyl-spiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0424] The title compound was obtained as described in EXAMPLE 9
starting with 2-iodo-5-methyl-aniline. MS(TSP+) m/z calcd for
[M-Cl].sup.+: 259, observed: 259
Example 11
6-Trifluoromethyl-1'-isopropyl-spiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0425] The title compound was obtained as described in EXAMPLE 9
starting with 3-amino-4bromo-benzotrifluoride. MS(TSP+) m/z calcd
for [M+H].sup.+: 439, 441, observed: 439, 441.
Example 12
4-Methylspiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0426] The title compound was obtained as described in EXAMPLE 9
starting with 2-Bromo-3-methylaniline. [M].sup.+: 217, observed:
217. It was converted to the hydrochloride.
Example 13
4-Methyl-1'-isopropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0427] The compound from the previous EXAMPLE was alkylated to the
title compound using PROCEDURE 1, Method A. .sup.13C-NMR
(CDCl.sub.13): .delta. 181.4, 141.0, 134.6, 130.4, 127.9, 125.2,
107.5, 61.0, 56.2, 54.1, 53.7, 48.6, 28.3, 21.2, 19.9, 19.5,
11.9.
Example 14
4-Methyl-1'-propylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0428] The compound from EXAMPLE 12 was alkylated to the title
compound. .sup.13C-NMR of the base (CDCl.sub.3): .delta. 181.5,
141.1, 134.7, 130.8, 127.8, 125.2, 107.5, 54.6, 50.9, 49.7, 28.6,
21.6, 19.8, 19.3, 15.9. MS(TSP+) m/z calcd for [M-Cl].sup.+: 259,
observed: 259.
Example 15
(S)-(+)-4-Methylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0429] The title compound was prepared by separating the
N-bocylated compound from EXAMPLE 12 on a Kirasil TBB column and
removing the Boc group from the collected product in 1M HCl in
methanol. [M-Cl].sup.+: 217, observed: 217.
Example 16
(S)-(+)-4-Methyl-1'-propylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0430] The compound from the previous EXAMPLE was alkylated to the
title compound using PROCEDURE 1, Method B.
Example 17
7-Fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0431] The title compound was prepared from 2-bromo-6-fluoroaniline
following the steps described in EXAMPLE 16 but deprotecting the
dibocylated unsaturated intermediate. [M-Cl].sup.+: 219, observed:
219.
Example 18
(S)-(+)-7-Fluorospiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0432] The title compound was prepared by separating the
N-bocylated precursor on a Kirasil TBB column and removing the Boc
group from the collected product in 1M HCl in methanol.
[M-Cl].sup.+: 219, observed: 219.
Example 19
Spiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0433] STEP A. t-Butyl
5-(2-bromophenylcarbamoyl)-1,2,5,6-tetrahydropyridi-
n-1-carboxylate. 2-Bromaniline was amidated to the title compound
as described in EXAMPLE 1. MS(TSP+) m/z calcd for
[M+NH.sub.4].sup.+: 398, 400, observed: 398, 400.
[0434] STEP B. t-Butyl
3-[(2-bromophenyl)-(t-butoxycarbonyl)-carbamoyl]-1,-
2,5,6-tetrahydropyridine-1-carboxylate. The compound from STEP A
was bocylated to the title compound by dissolving in DCM and add
di-tert-butyldicarbonate (1.2 equiv.), triethylamine (1.2 equiv.)
and dimethylaminopyridine (0.07 equiv). MS(TSP+) m/z calcd for
[M+NH.sub.4].sup.+: 498, 500, observed: 498, 500.
[0435] STEP C. Di-t-butyl
2-oxospiro[indoline-3,3'-(1,2,3,6-tetrahydropyri-
din)]-1,1'-dicarboxylate. Obtained according to EXAMPLE 1, STEP
C.
[0436] STEP D. Di-t-butyl
2-oxospiro[indoline-3,3'-piperidin]-1,1'-dicarbo- xylate. Obtained
according to EXAMPLE 1, STEP D.
[0437] STEP E. Spiro[indoline-3,3'-piperidin]-2-one hydrochloride.
The compound from the previous step was deprotected by dissolving
in 1M HCl in methanol and stirring for 1 hour. Evaporation of
solvents gave the title compound. .sup.13C-NMR (d.sub.4-MeOH):
180.6, 140.5, 129.5, 129.2, 122.8, 122.7, 110.5, 47.4, 43.7, 30.0,
23.5, 17.4 ppm
Example 20
1'-Ethylspiro[indoline-3,3'-piperidin]-2-one
[0438] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
acetaldehyde (5 equivalents). Yield: 45 mg (26%). .sup.13C NMR of
the HCl-salt (CD.sub.3OD): .delta.9.6, 19.8, 31.3, 46.3, 54.2,
54.3, 55.1, 111.5, 123.9, 124.4, 130.4, 131.3, 142.6, 182.3
Example 21
1'-Propyl-spiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0439] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
propionaldehyde (5 equivalents). Yield 65%.
Example 22
1'-Isopropylspiro[indoline-3,3'-piperidin]-2-one
[0440] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and acetone
(5 equivalents). Yield: 75%. .sup.13C NMR (CDCl.sub.3):
.delta.17.6, 17.7, 21.7, 32.1, 48.6, 48.8, 54.0, 54.8, 109.6,
121.6, 126.2, 127.2, 134.8, 140.1, 182.4; MS (CI, CH.sub.4): m/z
(rel. int.) 245 (M+1, 100)
Example 23
1'-Allylspiro[indoline-3,3'-piperidin]-2-one
[0441] The compound was prepared according to PROCEDURE 1, Method B
by reaction of spiro[indoline-3,3'-piperidin]-2-one with allyl
bromide (1.1 equivalents). .sup.13C NMR (CDCl.sub.3): .delta.21.2,
31.3, 48.4, 53.3, 58.1, 61.6, 109.5, 117.2, 121.6, .125.7, 127.4,
134.3, 135.1, 140.0, 181.6; MS (CI, CH.sub.4): m/z (rel. int.) 243
(M+1, 100)
Example 24
1'-Cyclopropylmethylspiro[indoline-3,3'-piperidin]-2-one
[0442] The compound was prepared according to PROCEDURE 1, Method A
by reaction of spiro[indoline-3,3'-piperidin]-2-one with 3 equiv.
of cyclopropanecarboxaldehyde. Yield: 90%. .sup.13C NMR
(CDCl.sub.3): .delta.3.8, 4.0, 8.3, 21.4, 31.8, 48.6, 53.3, 58.4,
63.6, 109.7, 121.7, 126.1, 127.4, 134.7, 140.0, 182.2; MS (CI,
CH.sub.4): m/z (rel. int.) 257 (M+1, 100)
Example 25
1'-Butylspiro[indoline-3,3'-piperidin]-2-one
[0443] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
butyraldehyde (10 equiv.). .sup.13C NMR (CDCl.sub.3): .delta.14.1,
20.6, 21.7, 29.1, 32.0, 49.0, 53.8, 58.5, 58.9, 109.9, 121.9,
126.4, 127.6, 134.9, 140.2, 182.4; MS (TSP): m/z (rel. int.)
260/259 (M.sup.+, 25/100)
Example 26
1'-s-Butylspiro[indoline-3,3'-piperidin]-2-one
[0444] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
2-butanone (3 equivalents). Yield: 46%. .sup.13C NMR (CDCl.sub.3):
.delta.11.5, 11.6, 13.3, 13.3, 21.7, 21.9, 26.4, 26.5, 32.1, 32.1,
46.1, 48.6, 49.0, 50.9, 52.4, 56.6, 61.2, 62.5, 109.6, 121.5,
121.6, 126.4, 126.5, 127.2, 134.7, 134.9, 140.1, 140.1, 182.4,
182.5; MS (CI, CH.sub.4): m/z (rel. int.) 259 (M+1, 100)
Example 27
1'-Isobutylspiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0445] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
isobutyraldehyde (3 equivalents). Purification on SiO.sub.2 twice
(eluent: DCM/MeOH). Yield: 88 mg. .sup.13C NMR (CD.sub.3OD):
.delta.21.2, 21.3, 22.7, 26.7, 32.9, 50.2, 55.4, 60.4, 68.3, 110.6,
122.6, 127.4, 128.6, 136.0, 141.8, 183.0; MS (CI, CH.sub.4): m/z
(rel. int.) 259 (M+1, 100)
Example 28
1'-Cyclobutylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride.
[0446] The compound was prepared according to PROCEDURE 1, Method A
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
cyclobutanone (5 equivalents). .sup.13C NMR of the HCl-salt
(CD.sub.3OD): .delta.14.4, 19.4, 26.1, 26.9, 31.2, 46.1, 50.4,
53.9, 61.6, 111.5, 123.9, 124.6, 130.4, 131.3, 142.6, 182.2; MS
(CI, CH.sub.4): m/z (rel. int.) 257 (M+1, 100).
Example 29
1'-Methoxyethylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0447] The compound was prepared according to PROCEDURE 1, Method B
by reaction with spiro[indoline-3,3'-piperidin]-2-one and
2-chloroethyl methylether (1.2 equivalents) and potassium iodide
(catalytic amount). EtOAc was used for extraction. Yield: 74%
.sup.13C NMR (CDCl.sub.3): .delta.21.8, 31.8, 48.8, 54.2, 58.0,
58.8, 59.2, 70.8, 109.8, 122.0, 126.4, 127.6, 134.8, 140.2, 182.0.
The HCl salt was prepared. MS (TSP): m/z (rel. int.) 262/261
(M.sup.+, 16/100).
Example 30
1'-Methylthioethylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0448] The compound was prepared according to PROCEDURE 1, Method B
by reaction with spiro[indoline-3,3'-piperidin]-2-one,
2-chloroethyl methylsulfide (1.2 equivalents) and potassium iodide
(catalytic amount). .sup.13C NMR (CDCl.sub.3): .delta.15.9, 21.7,
31.8, 31.9, 48.9, 53.3, 58.0, 58.8, 109.8, 122.1, 126.6, 127.7,
134.6, 140.2, 181.9.
[0449] The HCl salt was prepared. MS (EI, 70 eV): m/z (rel. int.)
278/277 (M.sup.+, 16/100).
Example 31
1'-Methoxypropylspiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0450] The compound was prepared according to PROCEDURE 1, Method B
by reaction with spiro[indoline-3,3'-piperidin]-2-one,
3-chloropropyl methyl ether (1.2 equivalents) and potassium iodide
(catalytic amount). .sup.13C NMR (CDCl.sub.3): .delta.21.8, 27.3,
32.0, 48.8, 53.8, 55.4, 58.8, 58.9, 71.1, 109.6, 122.0, 126.6,
127.7, 134.8, 140.0, 181.4.
[0451] The HCl salt was prepared. MS (TSP): m/z (rel. int.) 276/275
(M.sup.+, 15/100).
Example 32
(S)-1'-(3-Fluoropropyl)spiro[indoline-3,3'-piperidin]-2-one
hydrochloride
[0452] The racemic compound was prepared according to PROCEDURE 1,
Method B by reaction of spiro[indoline-3,3'-piperidin]-2-one with
1-bromo-3-fluoropropane (1.0 equivalent). EtOAc was used for
extraction. Yield: 69%. .sup.13C NMR (CDCl.sub.3): .delta.21.8,
28.0 (d, J.sub.F=20 Hz), 31.8, 48.9, 53.9, 54.3 (d, J.sub.F=5 Hz),
58.7, 81.7, 83.3, 110.0, 122.0, 126.2, 127.7, 134.7, 140.3, 182.1.
The racemate was separated on the Kirasil TBB column and the HCl
salt was prepared.
Example 33
(S)-(+)-1'-Propylspiro[indoline-3,3'-piperidin]-2-one
[0453] 1'-Propyl-1H-spiro[indole-3,3'-piperidin]-2-one (2.9 g, 11.9
mmol) and di-p-toluoyl-L-tartraric acid (4.6 g, 11.9 mmol) were
dissolved in ethanol (50 ml) at 40-50.degree. C. Water was added in
small portions (totally 50 ml) at the same temperature leaving a
clear solution which was slowly cooled to 5.degree. C. The crystals
(3.53 g) were collected the next day. A second crystallisation was
carried out in a similar manner using the same volume of solvents
yielding pure (S)-1'-propylspiro[indole-3,3'-piperidinium]-2-one
di-p-toluoyl-L-tartrate (3.2 g) which was converted to the
corresponding amine by a treatment with an excess of aqueous sodium
bicarbonate. The amine was extracted into ethyl acetate, the
extracts were dried over sodium sulfate and concentrated in vacuum.
The residue was dissolved in acetonitrile and treated with a 1.5
fold molar excess of hydrochloric acid.
[0454] Removal of the volatiles in vacuum and coevaparation with
acetonitrile yielded (S)-1'-propylspiro[indole-3,3'-piperidinium]-2
one hydrochloride (1.13 g, 78%),
[.alpha.].sub.D.sup.20+91.9.degree. (c 1.00, H.sub.2O). The
absolute configuration was established by X-ray crystallography of
the di-p-toluoyl-L-tartrate.
Example 34
(R)-(-)-1'-Propylspiro[indoline-3,3'-piperidin]-2-one
[0455] The mother liquid from the first crystallisation in the
previous EXAMPLE, consisting mostly of the other diastereomeric
salt was treated with NaHCO.sub.3/ethyl acetate to leave the
levorotatory amine. This was treated with 1 mol. eq. of
di-p-toluoyl-D-tartraric acid and the salt was crystallised from
50% aqueous ethanol. A similar further treatment as in EXAMPLE 27
yielded (R)-1'-propylspiro[indole-3,3'-piperidinium]-2-one
hydrochloride (1.09 g, 75%), [.alpha.].sub.D.sup.20 (c 1.00,
H.sub.2O).
Example 35
Spiro[indoline-3,3'-perhydroazepin]-2-one
[0456] STEP A. N-Benzyl-4-(3-indolyl)-butanamine. Lithium aluminum
hydride (4.8 g) was added to a solution of
N-benzyl-3-indolebutanamide (18.73 g) in dry THF (200 mL) at
nitrogen atmosphere and at 0.degree. C. After stirring at reflux
for 15 h and work-up with sodium hydroxide the title compound was
obtained as pale yellow crystals (16.4 g).
[0457] STEP B. 3-(4-(Benzylamino)-butyl)-indolin-2-one. Conc
hydrochloric acid (90 mL) was added to a solution of the compound
from the previous step in DMSO (38 mL) and MeOH (8 mL). After
stirring for 30 min at 0.degree. C. and 30 min at room temperature
the mixture was poured onto ice followed by extractive work-up. The
title compound was obtained as a crude orange oil (16.2 g).
[0458] STEP C. 1'-Benzylspiro[indoline-3,3'-perhydroazepin]-2-one.
A solution of the compound from the previous step (15.5 g) was
cyclised via a Mannich reaction following the procedure described
in J Med Chem 1976, 19, 892. Evaporation, extractive work-up and
purification on silica gave the title compound as a yellow oil (2.4
g).
[0459] STEP D. Spiro[indoline-3,3'-perhydroazepin]-2-one
hydrochloride. The compound from the previous step was hydrogenated
in acetic acid over 10% Pd/C at 40 psi H.sub.2 for 48 h.
Evaporation and extractive work-up gave the title compound as a
yellow solid (1.51 g). MS (TSP+) m/z: 217 (M+H.sup.+, 100) which
was converted to the title compound.
EXAMPLE 36
1'-Propylspiro[4-azaindoline-3,3'-piperidin]-2-one
[0460] STEP A. tert-Butyl
3-[(2-bromo-3-pyridyl)carbamoyl]-1,2,5,6-tetrahy-
dropyridine-1-carboxylate. 2-Bromo-3-pyridineamine (3.0 g, 17.3
mmol) and 1,2,5,6-tetrahydro-1,3-pyridinedicarboxylic acid
1-tert-butyl ester 3-methyl ester (5.05 g, 20.8 mmol) were
dissolved in DCM (80 ml). To the solution trimethylaluminium (26
mmol, 2M solution) was slowly added at 0.degree. C. The mixture was
refluxed overnight. Work-up and purification on silica gel using
60% ethyl acetate in heptane as an eluent gave 5.65 g (85%) of the
title compound.
[0461] STEP B. tert-Butyl
3-[N-(2-bromo-3-pyridyl)-N-(tert-butoxycarbonyl)-
carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. The compound
from STEP A was dissolved in DCM and di-tert-butyl-dicarbonate
(3.85 g, 17.6 mmol) was added followed by triethylamine (2.51 ml,
18.0 mmol) and dimethylaminopyridine (0.17 g, 1.4 mmol). After
stirring the mixture for 1 h at room temperature methanol was added
and the volatiles were removed in vacuum. Purification of the
product on a column packed with silica gel using 40% ethyl acetate
in heptane as an eluent afforded 6.74 g, (95%) of the title
compound.
[0462] STEP C. Di-t-butyl
2-oxo-1,1'-spiro[4-azaindoline-3,3'-(1,2,3,6-tet-
rahydropyridin)]-1,1'-dicarboxylate. The compound from STEP B was
dissolved in acetonitrile (80 ml), palladium acetate (0.37 g, 1.67
mmol) and triphenylphosphine (1.0 g, 3.8 mmol) were added and
finally triethylamine (2.9 ml, 20.8 mmol). The mixture was refluxed
under nitrogen for 2.5 hours. Work-up gave the title compound (4.13
g, 74%).
[0463] STEP D. Di-t-butyl
2-oxo-1,1'-spiro[4-azaindoline-3,3'-piperidin]-1-
,1'-dicarboxylate. The compound from STEP C was hydrogenated in
methanol over 10% Pd/C at 50 psi H.sub.2 for 3 h. Purification on a
column packed with silica gel using 60% ethyl acetate in heptane as
an eluent gave the title compound (82%).
[0464] STEP E. 1'-Propylspiro[4-azaindoline-3,3'-piperidin]-2-one.
The compound from STEP D was deprotected using a mixture of 36%
hydrochloric acid, methanol and dioxane (1:1:5 volume per cent) at
room temperature for 10 h. The volatiles were removed and the crude
spiro[4-aza-indole-3,3'-piperidin]-2-one was alkylated according to
PROCEDURE 1, Method A. The product was purified on a column with
silica gel using 10-20% methanol in ethyl acetate as an eluent to
give the title compound (57%). .sup.13C NMR, .delta. ppm: 12.9,
20.6, 22.0, 31.0, 49.0, 55.2, 58.1, 62.0, 117.3, 123.4, 136.6,
143.6, 155.4, 181.7.
Example 37
1'-Butylspiro[4-azaindoline-3,3'-piperidin]-2-one
[0465] The title compound was synthesised according to the
procedure described in EXAMPLE 29 using butanal. .sup.13C NMR,
.delta. ppm: 15.1, 21.8, 22.0, 29.6, 31.0, 49.0, 55.3, 58.2, 60.0,
117.2, 123.4, 136.6, 143.7, 155.4, 181.7.
Example 38
1'-s-Butylspiro[4-aza-indoline-3,3'-piperidin]-2-one
[0466] Was synthesised according to EXAMPLE 30 using sec-butanal.
.sup.13C NMR, .delta. ppm: 21.6, 21.9, 22.0, 26.3, 30.9, 49.1,
55.8, 58.4, 67.8, 117.2, 123.4, 136.5, 143.6, 155.4, 181.7.
Example 39
1'-Propyl-5-chlorospiro[7-aza-indoline-3,3'-piperidin]-2-one
[0467] STEP A. 3-Bromo-5-chloro-2-pyridineamine. To
5-chloro-2-pyridineamine (3 g,23.3 mmol) dissolved in acetic acid
(40 ml) a solution of bromine (1.29 ml, 25 mmol) in acetic acid was
added dropwise at 10.degree. C. The mixture was stirred for 2 h at
room temperature and then concentrated. Work-up and purification on
a column packed with silica gel using 40% ethyl acetate in heptane
as an eluent yielded the title compound as a colourless powder
(3.58 g, 74%).
[0468] STEP B. t-Butyl
3-[N-(3-bromo-5-chloro-2-pyridyl)-N-(tert-butoxycar-
bonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. The
compound from STEP A was treated in a similar manner as was
described in EXAMPLE 29, STEPS A and B affording the title compound
in good yield.
[0469] STEP C. Di-t-butyl
5-chloro-2-oxo-1,1'-spiro[7-azaindoline-3,3'-pip-
eridin]-1,1'-dicarboxylate. The previous amide was cyclized as
described in EXAMPLE 29, STEP C and the resulting product was
hydrogenated in methanol under 50 psi H.sub.2 over 10% Pd/C for 20
hours to give the title compound after chromatografic separation on
silica gel. The dechlorinated compound was also obtained in 40%
yield.
[0470] STEP D. 5-Chloro-spiro[7-azaindoline-3,3'-piperidin]-2-one.
The cyclized product from the previous step was deprotected as
described in EXAMPLE 29.
[0471] STEP E.
1'-Propyl-5-chloro-spiro[7-azaindoline-3,3'-piperidin]-2-on- e. The
compound from the previous step was converted to the title compound
as described in EXAMPLE 29. .sup.13C NMR, .delta. ppm: 12.8, 21.0,
22.8, 32.3, 49.9, 54.5, 59.3, 61.4, 118.6, 119.3, 135.2, 146.7,
156.7, 181.1.
Example 40
1'-Propylspiro[7-azaindoline-3,3'-piperidin]-2-one
[0472] The dechlorinated product from EXAMPLE 33, Step C, was
deprotected and alkylated as described in the previous exampel.
.sup.13C NMR, .delta. ppm: 12.7, 20.8, 22.7, 32.2, 50.3, 54.1,
59.3, 61.4, 123.3, 127.0, 135.8, 145.4, 154.3, 180.4.
Example 41
1'-Propyl-6-methylspiro[7-azaindoline-3,3'-piperidin]-2-one
[0473] STEP A. 2-Amino-6-methylpyrid-3-yl
trifluoromethanesulfonate. To a stirred suspension of
2-amino-6-methylpyridin-3-ol (2 g) in DCM (50 ml) containing
triethylamine (2.2 g), trifluoromethanesulfonic anhydride (5.3 g)
was added under N.sub.2 at -78.degree. C. After the mixture became
homogeneous, it was allowed to warm to -20.degree. C. and then
quenched with aqueous NaHCO.sub.3. Work-up by extraction into
chloroform purification on silica gel using 40% ethyl acetate in
heptane as an eluent afforded the title compound (86%).
[0474] STEP B.
4-(6-Methyl-3-trifluoromethanesulfonyloxypyrid-2-ylcarbamoy-
l)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester. The
compound from STEP A was treated in a similar manner as was
described in EXAMPLE 29, STEP A affording the title compound in 42%
yield.
[0475] STEP C. t-Butyl
6-methyl-2-oxo-spiro[7-azaindoline-3,3'-(1,2,3,6-te-
trahydropyridin)]-1'-carboxylate. The compound from STEP B was
treated in a similar manner as was described in EXAMPLE 29, STEP. C
affording the title compound in 76% yield.
[0476] STEP D. t-Butyl
6-methyl-2-oxo-spiro[7-azaindoline-3,3'-piperidin]--
1'-carboxylate. The compound from STEP C was treated in a similar
manner as was described in EXAMPLE 29, STEP D affording the title
compound in 85% yield.
[0477] STEP E.
6-Methyl-1'-propylspiro[7-azaindoline-3,3'-piperidin]-2-one
dihydrochloride. The compound from STEP D was treated in a similar
manner as was described in EXAMPLE 29, STEP E affording the title
compound in 66% yield. .sup.13C NMR, .delta. ppm: 12.8, 21.0, 22.9,
24.2, 32.4, 49.7, 54.7, 59.6, 61.4, 117.5, 127.0, 135.4, 156.4,
156.9, 181.5. It was converted to the dihydrochloride by treatment
with HCl in ethanol and evaporation of solvents.
Example 42
1'-Propylspiro[isoindoline-3,3'-piperidin]-1-one hydrochloride
[0478] STEP A. 2-Bromo-N-(3-pyridyl)benzamide. To a solution of
2-bromobenzoylchloride (11.6 g) in dry pyridine (50 ml) at rt.,
3-aminopyridine (5.0 g) dissolved in dry pyridine was added. After
stirring for 12 hours and extractive work-up 7.77 g of the title
product was obtained as white crystals. MS(ESP+) m/z: 279
(M+H+,98), 277 (M+H+, 100).
[0479] STEP B.
2-Bromo-N-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)benzamid- e. To
a stirred solution of the compound from Step A (6.0 g) in dry
toluene (100 ml) propylbromide (13.0 g) was added. The reaction
mixture was stirred at 80.degree. C. for 16 hours. The precipitated
oil was dissolved in MeOH (100 ml) and sodium borohydride (6.0 g)
was added slowly at rt. After 3 hours of reaction time, work-up and
chromatography on silica gel with ethyl acetate/n-heptane as the
eluent 6.65 g of the title product was obtained as an oil. MS(TSP+)
m/z: 325 (M+H+, 92), 323 (M+H+, 100).
[0480] STEP C.
2-Iodo-N-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)benzamide- . To a
stirred solution of 2-iodo-N-pyridin-3-ylbenzamide (8.32 g) in dry
toluene (200 ml) was added benzyl bromide (5.1 g). The reaction
mixture was stirred at 100 .degree. C. for 16 hours. The solvent
was decanted from the precipitated crystals which were dissolved in
MeOH (150 ml) and the treated with sodium borohydride to give 7.9 g
of the title compound as white-yellow crystals. MS(TSP+) m/z: 419
(M+H+, 100).
[0481] STEP D. 1'-Propylspiro[isoindoline-3,3'-piperidin]-1-one
hydrochloride. The compound from STEB B (6.60 g) was cyclised
according to the general Heck procedure described in EXAMPLE 1 to
give an oil which was chromatographed on silica gel with ethyl
acetate/n-heptane as the eluent to give 830 mg
1'-propylspiro-[isoindoline-3,3'-1,2,3,6-tetrahydro- pyridin]-1-one
as an oil. This compound was hydrogenated as described in EXAMPLE 1
yielding the free base of the title compound as white crystals. The
title compound was also prepared from cyclization of the STEP C
compound followed by hydrogenation-debenzylation plus propylation.
.sup.13C NMR (CDC13): .delta. 169.44, 150.10, 131.77, 131.58,
128.51, 124.14, 121.56, 62.74, 60.87, 60.26, 53.24, 34.88, 23.34,
19.00, 11.82.; MS(TSP+) m/z: 245 (M+H+, 100); MS(CI, NH3): 245
(M+H+, 100), 180 (3). Mp: 110-112.degree..
[0482] The title compound was prepared by treating it with HCl in
Et2O. Anal. Calcd for C15H21ClN2O: C, 64.13; H, 7.53; N 10.01
Found: C, 64.25; H, 7.6; N, 10.0.
Example 43
Spiro[3,4-dihydro-1H-quinoline-3,3'-piperidin]-2-one
hydrochloride
[0483] STEP A. 1-t-Butyl 3-ethyl
3-(2-nitrobenzyl)-1,3-piperidinedicarboxy- late. To a solution of
ethyl 1-t-butyloxycarbonyl-3-piperidinecarboxylate (1.5 g) in THF
(10 ml) at -78.degree. C. was added lithium hexamethyldisilazide
(8.74 ml of a 1M solution in THF). A solution of 2-nitrobenzyl
bromide. (1.5 g) in THF (5 ml) was added dropwise at -78.degree. C.
and the reaction mixture was allowed to reach room temperature.
Work-up and chromatography on silica gel with ethyl
acetate/petroleum benzine 5:1 as eluent gave 1.3 g of the title
compound.
[0484] STEP B. 1'-t-Butyl
spiro[3,4-dihydro-1H-quinoline-3,3'-piperidin]-2-
-one-1-carboxylate. To a solution of 1-t-butyl 3-ethyl
3-(2-nitrobenzyl)-1,3piperidinedicarboxylate (1.2 g) in methanol
(25 ml) 10% Pd/C (0.3 g) was added and the mixture was hydrogenated
at 30 psi for 2 h. The mixture was filtered and concentrated to
yield 0.95 g of the title compound.
[0485] STEP C. Spiro[3,4-dihydro-1H-quinoline-3,3'-piperidin]-2-one
hydrochloride. The compound (0.90 g) from STEP B was debocylated in
ethyl acetate HCl-diethyl ether and the deprotected amine was
precipitated as the hydrochloride salt. .sup.13C NMR (CD.sub.3OD,
400 MHz): .delta. 20.24, 29.95, 37.14, 38.83, 45.01, 50.28, 116.26,
122.08, 124.74, 129.00, 129.83, 137.42, 175.17.
Example 44
1'-Propylspiro [3,4-dihydro-1H-quinoline-3,3'-piperidin]-2-one
hydrochloride
[0486] Spiro[3,4-dihydro-(1H)-quinoline-3,3'-piperidin]-2-one (0.55
g) was propylated according to the general PROCEDURE 1, Method A.
The crude product was purified by flash chromatography on silica
gel with DCM/methanol 9:1 as eluent to give 0.44 g of the title
compound as the free base. .sup.13C NMR (CDCl.sub.3, 400 MHz):
.delta. 11.74, 19.85, 21.18, 29.12, 33.28, 40.82, 54.47, 57.34,
60.51, 114.67, 122.90, 123.03, 127.17, 128.59, 136.48, 175.64. The
product was converted to the hydrochloride by dissolving the base
in di ethyl ether and precipitate with HCl in Et.sub.2O.
Example 45
[0487] 1'-Isopropylspiro[indoline-3,3'-piperidine]hydrochloride. To
a solution of 1'-isopropylspiro[indoline-3,3'-piperidin]-2-one (0.2
g) in THF (10 ml) borane-dimethyl sulfide complex in THF (2 M
solution, 0.90 ml) was added. The reaction mixture was refluxed for
1 h. The solvent was evaporated in vacuo and the residue was
refluxed with one equivalent of HCl (g) in ethanol for 30 minutes.
After work-up the residue was purified by flash chromatography on
silica gel with ethyl acetate as eluent to yield 0.12 g of the
base. 13C NMR (CDCl3, 400 MHz): .delta. 16.3, 19.6, 23.7, 35.1,
46.2, 50.2, 54.9, 57.2, 57.3, 109.7, 118.2, 123.2, 128.0, 135.9,
151.8. It was converted to the hydrochloride with HCl in ether.
Example 46
1'-Methylspiro[2,3-dihydrobenzofuran-3,3'-piperidine]hydrochloride
[0488] STEP A. 2-Iodophenyl
(1-methyl-1,2,5,6-tetrahydro-3-pyridinyl)methy- l ether. To an
ice-cooled stirred solution of triphenylphosphine (1.54 g) and
diethyl azodicarboxylate (0.92 ml) in THF (20 ml) 2-iodophenol
(1.27 g) and (1-methyl-1,2,5,6-tetrahydro-3-pyridyl)methanol (0.5
g) were added. The mixture was stirred for 72 h at room
temperature. The solvent was evaporated and the residue was
purified by chromatography on silica gel with first ethyl acetate
and then 10% methanol in DCM as eluent to yield 0.98 g of the title
compound.
[0489] STEP B.
1'-Methylspiro[2,3-dihydrobenzofuran-3,3'-(1,2,3,6-tetrahyd-
ropyridin)]. The prevoius compound (0.42 g) was cyclized following
the procedure in EXAMPLE 1 using tri-o-tolylphosphine to yield 0.2
g of the title compound.
[0490] STEP C.
1'-Methylspiro[2,3-dihydrobenzofuran-3,3'-piperidine]hydroc-
hloride. To a solution of the previous compound (0.2 g) in acetic
acid (10 ml) 10% Pd/C (0.1 g) was added and the mixture was
hydrogenated in a Parr apparatus at 50 psi for 6 h. The residue
after filtering and evaporation of solvents gave 0.2 g of the title
compound. 13C NMR (CDCl3, 400 MHz): .delta. 22.9, 34.1, 46.1, 46.6,
55.5, 65.0, 81.0, 109.6, 120.1, 123.1, 128.5, 133.9, 158.5. It was
converted to the hydrochloride.
Example 47
1'-Propylspiro[2,3-dihydrobenzofuran-3,3'-piperidine]hydrochloride
[0491] STEP A.
Spiro[2,3-dihydrobenzofuran-3,3'-(1,2,3,6-tetrahydropyridin- e)].
To a stirred solution of the product from EXAMPLE (0.32 g) in
1,2-dichloroethane (20 ml) 1-chloroethyl chloroformate (0.46 g) was
added and the mixture was refluxed for 36 h. After concentration
methanol (10 ml) was added and the mixture was refluxed for 4 h.
Concentration gave 0.3 g of the product.
[0492] STEP B.
1'-Propylspiro[2,3-dihydrobenzofuran-3,3'-(1,2,3,6-tetrahyd-
ropiperidine)]. The previous compound was propylated according to
PROCEDURE 1, METHOD B giving the title compound in 60% yield.
[0493] STEP C.
1'-Propylspiro[2,3-dihydrobenzofuran-3,3'-piperidine]hydroc-
hloride. The previous compound was hydrogenated at 50 psi for 6 h
over Pd/C. Work-up yielded the title compound. 13C NMR
(CDCl.sub.3): .delta. 12.1, 20.2, 22.8, 34.8, 46.2, 54.1, 60.5,
63.0, 81.8, 109.9, 120.3, 123.2, 128.6, 133.9, 159.5. It was
converted to the hydrochloride.
Example 48
Spiro[3,4-dihydro-1H-quinoline-4,3'-piperidin]-2-one
hydrochloride
[0494] STEP A. N-(2-Iodophenyl)-2-(4-pyridinyl)acetamide. A
solution of 3-pyridylacetic acid (2.0 g) and triethylamine (2.0 mL)
in dry THF (20 mL) was treated at -10.degree. C. with isobutyl
chloroformate (2.0 mL). After 10 minutes at -10.degree. C., a
solution of 2-iodo-aniline (3.6 g) in THF (10 mL) was added. The
reaction mixture was allowed to stir while slowly warming to room
temperature. The solvent was evaporated, and the residue was
partitioned between ethyl acetate and saturated NaHCO.sub.3
solution. The organic layer was dried over MgSO.sub.4, filtered,
the solvent was evaporated and the residual oil was purified by
flash chromatography to yield 1.0 g of the title product. MS (TSP+)
m/z [M+H].sup.+: 339.
[0495] STEP B.
2-(1-Benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-N-(2-iodophenyl-
)acetamide. Benzyl bromide (1.0 g) was added to a solution of
N-(2-iodophenyl)-2-(4-pyridinyl)acetamide (1.0 g) in acetone. The
mixture was stirred at reflux over night. The resulting viscous oil
was decanted and used without further purification. To a stirred
solution of the pyridinium salt in methanol (20 mL) was added
portionwise NaBH.sub.4 (0.14 g) at 0.degree. C. during 1 hour. On
completion of the addition, the resulting mixture was allowed to
warm to room temperature and stirred overnight. Water was added
carefully and the resulting mixture was concentrated in vacuo. The
residue was extracted twice with ethyl acetate. The organic layer
was dried over MgSO.sub.4, filtered, the solvent was evaporated and
the residual oil was purified by flash chromatography to yield 1.0
g of the title product. MS (TSP+) m/z [M+H].sup.+: 433.
[0496] STEP C.
1'-Benzylspiro[3,4-dihydro-1H-quinoline-4,3'-1,2,3,6-tetrah-
ydropyridin]-2-one. The product from STEP B (0.7 g) was dissolved
in acetonitrile (20 mL) and triethylamine (0.50 mL) under
N.sub.2-atmosphere. After 0.5 h tri-o-tolylphosphine (90 mg) and
palladium acetate (36 mg) were added in one portion. The mixture
was refluxed for 18 hours under N.sub.2-atmosphere. The crude
product was purified by chromatography on silica gel and eluted
with ethyl acetate to give the title compound (0.3 g) as a yellow
oil. MS (TSP+) m/z [M+H].sup.+: 305.
[0497] STEP D. Spiro[3,4-dihydro-1H-quinoline-4,3'-piperidin]-2-one
hydrochloride. The product from STEP C was hydrogenated in glacial
acetic acid (20 mL) using 10% Pd/C and H.sub.2 (3.5 atm) for 18
hours. The catalyst was filtered off and the solution was
concentrated in vacuo. The residue was dissolved in DCM and
saturated NaHCO.sub.3 solution and the water layer was extracted
three times with DCM. The organic layer was dried over MgSO.sub.4,
filtered, the solvent was evaporated to yield 0.13 g of the title
compound as the free base. .sup.13C NMR (CDCl.sub.3, 400 MHz):
.delta.22.0, 33.3, 36.2, 38.3, 46.5, 54.3, 116.1, 123.3, 124.9,
127.6, 130.5, 136.6, 171.3. The product was converted to the
hydrochloride by dissolving the base in ethyl acetate and
precipitate with HCl in Et.sub.2O.
Example 49
(S)-(-)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e dihydrochloride
[0498] STEP A. t-Butyl
3-(3-bromo-5-methyl-2-pyridylcarbamoyl)-1,2,5,6-tet-
rahydropyridine-1-carboxylate. It was prepared analogously to
EXAMPLE 36, STEP A. in a yield of 53%.
[0499] STEP B. t-Butyl
3-[N-(3-bromo-5-methyl-2-pyridyl)-N-(tert-butoxycar-
bonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. The
compound from STEP A was converted to the semisolid title compound
in a yield of 50% as described in EXAMPLE 36, STEP B.
[0500] STEP C. Di-t-butyl
5-methyl-2-oxo-1,1'-spiro[7-azaindoline-3,3'-(1,-
2,3,6-tetrahydropyridin)]-1,1'-dicarboxylate. The compound from
STEP B was treated as described in EXAMPLE 36, STEP C to give the
title compound in 80% yield.
[0501] STEP D. t-Butyl
5-methyl-2-oxo-1,1'-spiro[7-azaindoline-3,3'-(1,2,3-
,6-tetrahydropyridin)]-1,1'-carboxylate. The compound from STEP C
was treated in methanol at reflux with 10 equivalents of ammonium
acetate for 2 h. The residue after evaporation of solvent was
purified by SGC (EtOAc:isohexanes 1:1 to pure EtOAc) to give the
title compound as a white solid. Due to the presence of rotamers it
was difficult to obtain good NMR spectra.
[0502] STEP E. (S)-(+)-t-Butyl
5-methyl-2-oxo-1,1'-spiro[7-azaindoline-3,3-
'-(1,2,3,6-tetrahydropyridin)]-1'-carboxylate. The compound from
STEP D was chromatographically resolved on a Kirasil TBB column
using heptane/2-PrOH 9:1 as an eluent and recycling the eluate
twice.
[0503] STEP F.
(S)-(-)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydr-
opyridin)]-2-one dihydrochloride. The compound from STEP E, second
peak, was deprotected using 0.5 M HCl in methanol-ether at room
temperature for 15 h. Evaporation of solvents gave the title
compound in quantitative yield. It is tentatively assigned the S
configuration based on its elution pattern on the chiral column. MS
(TSP+) m/z [M+H]+: 216.
[0504] [.alpha.].sub.589.sup.22 -36.degree. (c 1.0, MeOH).
Example 50
(R)-(+)-5-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e dihydrochloride
[0505] The material from STEP E, first peak, was deprotected
similarly. 13C-NMR (d4-MeOH): 177.6, 152.5, 143.0, 135.6, 131.7,
129.8, 127.4, 123.7, 47.7, 45.6, 42.2, 17.9 ppm.
[.alpha.].sub.589.sup.22+39.degree. (c 1.04, MeOH).
Example 51
(S)-5,6-Dimethylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e hydrochloride
[0506] STEP A. t-Butyl
3-(3-bromo-5,6-dimethyl-2-pyridylcarbamoyl)-1,2,5,6-
-tetrahydropyridine-1-carboxylate. It was prepared analogously to
EXAMPLE 36, STEP A starting from
3-bromo-5,6-dimethyl-2-pyridineamine (J. Heterocycl. Chem. 1994,
31, 1641-5) in a yield of 57% after SGC (EtOAc: heptane
1:1.fwdarw.4:1). MS (TSP+) m/z [M+1].sup.+: 410 and 412.
[0507] STEP B. t-Butyl
3-[N-(3-bromo-5,6-dimethyl-2-pyridyl)-N-(tert-butox-
ycarbonyl)carbamoyl]-1,2,5,6-tetrahydropyridine-1-carboxylate. The
compound from STEP A was converted to the crude title compound in a
yield of 100% as described in EXAMPLE 36, STEP B. MS (TSP+) m/z
[M-Boc+1].sup.+410 and 412.
[0508] STEP C. Di-t-butyl
5,6-dimethyl-2-oxo-1,1'-spiro[7-azaindoline-3,3'-
-(1,2,3,6tetrahydropyridin)]-1,1'-dicarboxylate. The compound from
STEP B was treated as described in EXAMPLE 36, STEP C to give the
title compound in 70% yield.
[0509] STEP D. t-Butyl
5,6-dimethyl-2-oxo-1,1'-spiro[7-azaindoline-3,3'-(1-
,2,3,6-tetrahydropyridin)]-1'-carboxylate. The compound from STEP C
was treated in methanol at reflux with 10 equivalents of ammonium
acetate for 2 h. The residue after evaporation of solvent was
purified by SGC (EtOAc:heptane 1:1) to give the title compound as a
white solid. Due to the presence of rotamers it was difficult to
obtain good NMR spectra. MS (TSP+) m/z [M+1].sup.+330.
[0510] STEP E. (S)-t-Butyl
5,6-dimethyl-2-oxo-1,1'-spiro[7-azaindoline-3,3-
'-(1,2,3,6-tetrahydropyridin)]-1'-carboxylate. The compound from
STEP D was chromatographically resolved on a Kirasil TBB column
using heptane/2-PrOH 95:5 as an eluent and recycling the eluate
twice.
[0511] STEP F.
(S)-5,6-Dimethylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydr-
opyridin)]-2-one dihydrochloride. The compound from STEP E, second
peak (190 mg), was deprotected using 0.5 M HCl in methanol-ether at
room temperature for 15 h. Evaporation of solvents gave the title
compound in quantitative yield. It is tentatively assigned the S
configuration based on its elution pattern on the chiral column. MS
(TSP+) m/z [M+H].sup.+: 230. .sup.1H-NMR (d.sub.4-MeOH): 7.80 (s,
1H), 6.11 (d, 1H), 5.54 (d, 1H), 3.75 (m, 2H), 3.52 (dd, 2H), 2.42
(s, 3H), 218 (s, 2H).
[0512] The following EXAMPLES 52-81 were prepared analogously to
EXAMPLE 49 and 51 starting with an aniline or other aromatic amine.
The mono-Boc protected intermediates were separated using a Kirasil
TBB (PROCEDURE 2) or Chiralpak AD column. All resolved compounds
obtained from the last eluting peak on the Kirasil TBB column are
assumed to have the S configuration, and vice versa.
Example 52
(S)-5-Chlorospiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
dihydrochloride
[0513] .sup.13C-NMR (D.sub.2O), .delta.: 42.1, 45.5, 48.0, 123.7,
126.2, 126.7, 127.7, 135.2, 146.4, 154.9, 180.0 ppm.
Example 53
(R)-5-Chlorospiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
dihydrochloride
[0514] MS (TSP+) m/z [M+H].sup.+: 235
Example 54
(R)-6-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
dihydrochloride
[0515] .sup.13C-NMR (D.sub.2O): .delta.20.3, 42.0, 45.2, 47.3,
120.5, 123.1, 124.7, 127.3, 140.2, 151.7, 153.4, 179.3 ppm.
Example 55
(S)-6-Methylspiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
dihydrochloride.
[0516] MS (TSP+) m/z [M+H].sup.+: 216
Example 56
(S)-7-Fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0517] .sup.13C-NMR (d.sub.4-MeOH): 179.7, 149.9, 147.5, 133.3,
131.0, 130.4, 126.3, 125.9, 125.1, 125.0, 121.16, 121.13, 117.9,
117.7, 109.5, 47.0, 42.6, 30.7 ppm.
Example 57
(R)-7-Fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0518] MS (TSP+) m/z [M+H].sup.+: 219
Example 58
(S)-4-Methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0519] .sup.13C-NMR (d.sub.4-MeOH): 180.1, 143.4, 137.0, 131.0,
127.1, 126.4, 126.3, 125.2, 109.5, 45.6, 42.8, 17.8 ppm.
Example 59
(R)-4-Methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0520] MS (TSP+) m/z [M+H].sup.+: 215
Example 60
(S)-Spiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0521] MS (TSP+) m/z [M+H].sup.+: 201. .sup.13C-NMR (d.sub.4-MeOH):
.delta.180.0, 141.6, 131.1, 127.1, 125.5, 125.4, 124.3, 117.2,
47.2, 43.0 ppm.
Example 61
(R)-Spiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0522] MS (TSP+) m/z [M+H].sup.+: 201
Example 62
(R)-5,7-Difluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0523] MS (TSP+) m/z [M+H].sup.+: 237.
Example 63
(S)-5,7-Difluorospiro
[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one hydrochloride
[0524] MS (TSP+) miz [M+H].sup.+: 237
Example 64
(R)-5-Trifluoromethoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-o-
ne hydrochloride
[0525] .sup.13C-NMR (d.sub.4-MeOH): 179.9, 146.1, 142.4, 132.1,
126.0, 125.9, 124.3, 123.2, 120.7, 119.6, 112.6, 111.8, 46.6, 42.6,
30.7 ppm.
Example 65
(S)-5-Trifluoromethoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-o-
ne hydrochloride
[0526] MS (TSP+) m/z [M+H].sup.+: 285
Example 66
(R)-5-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0527] MS (TSP+) m/z [M+H].sup.+: 235. .sup.1H-NMR (d.sub.4-MeOH):
7.4 (m, 1H), 7.37 (d, 1H), 6.97 (d, 1H), 6.22 (d, 1H), 5.65 (d,
1H), 3.90 (m, 1H), 3.60 (m,1H).
Example 67
(S)-5-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0528] MS (TSP+) m/z [M+H].sup.+: 235
Example 68
(R)-5-Chloro-7-fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e hydrochloride
[0529] MS (TSP+) m/z [M+H].sup.+: 253. .sup.1H-NMR (d.sub.4-MeOH):
7.3 (m, 2H), 6.2 (m, 1H), 5.7 (m, 1H), 3.9 (m, 1H), 3.6 (m,1H).
Enantiomeric purity 98.0%.
Example 69
(S)-5-Chloro-7-fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e hydrochloride
[0530] MS (TSP+) m/z [M+H].sup.+: 253.
Example 70
(R)-7-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0531] MS (TSP+) m/z [M+H].sup.+: 235. .sup.13C-NMR (d.sub.4-MeOH):
180.0, 141.6, 132.5, 131.4, 126.7, 126.1, 125.6, 124.3, 117.2,
47.2, 43.0 ppm.
Example 71
(S)-7-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0532] MS (TSP+) m/z [M+H].sup.+: 235.
Example 72
(S)-6-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0533] MS (TSP+) m/z [M+H].sup.+: 235. .sup.13C-NMR (d.sub.4-MeOH):
180.4, 145.1, 137.0, 129.4, 127.0, 126.8, 126.0, 124.4, 112.6,
47.1, 43.0 ppm.
Example 73
(S)-5-Methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0534] .sup.13C-NMR (CDCl.sub.3) .delta.180.2, 140.6, 134.1, 131.2,
130.4, 127.0, 125.9, 125.2, 111.5, 48.0, 47.1, 42.7, 21.1. MS(ESP+)
m/z calcd for [M-Cl].sup.30 : 215, observed: 215.
Example 74
(S)-5-Fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0535] MS (TSP+) m/z [M+H].sup.+: 219. .sup.1H-NMR (d.sub.4-MeOH):
7.1, 7.0, and 6.9 (3 m, 3H), 6.18 (d, 1H), 5.57 (d, 1H), 3.85 (dd,
2H), 3.52 (s, 2H).
Example 75
(S)-4-Chlorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0536] MS (TSP+) m/z [M+H].sup.+: 235.
Example 76
(R)-4-Methoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0537] MS (TSP+) m/z [M+H].sup.+: 231. .sup.13C-NMR (CDCl.sub.3)
.delta.179.7, 157.7, 144.2, 132.6, 126.5, 124.5, 115.8, 107.2,
105.1, 56.3, 48.1, 45.8, 42.7.
Example 77
(R)-6-Methoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0538] MS (TSP+) m/z [M+H].sup.+: 231.
Example 78
(S)-7-Fluoro-5-methylspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-on-
e hydrochloride
[0539] MS (TSP+) m/z [M+H].sup.+: 233.
Example 79
5-Fluorospiro[7-azaindoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0540] MS (TSP+) m/z [M+H].sup.+: 220.
Example 80
(S)-6-Fluorospiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0541] MS (TSP+) m/z [M+H].sup.+: 219. .sup.1H NMR (CD.sub.3OD):
.delta.7.1 (m, 1H), 6.6 (m, 2H), 6.0 (d, 1H), 5.5 (d, 1H), 3.7 (s,
2H), 3.1 (s, 1H), 1.1 (s, 1H).
Example 81
(S)-5-Methoxyspiro[indoline-3,3'-(1,2,3,6-tetrahydropyridin)]-2-one
hydrochloride
[0542] MS (TSP+) m/z [M+H].sup.+: 231. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta.6.9 (d, 1H), 6.8 (dd, 1H), 6.7 (d, 1H), 6.1 (d, 1H),
5.6 (d, 1H), 3.9 (s, 2NH), 3.8 (s, 2H), 3.5 (d, 1H), 3.4 (d, 1H),
3.1 (s, 3H).
Example 82
6H-4,5-Dihydro-2-methylspiro[pyrrolo[2,3-c]pyrazole-4,3'-(1,2,3,6-tetrahyd-
ropyridin)]-5-one hydrochloride
[0543] The compound is made from commercially available
3-amino-4-bromo-1-methylpyrazole following the general procedure
via Heck cyclisation described in Example 49.
Example 83
6H-4,5-Dihydro-2-methylspiro[thieno[2,3-b]pyrrole-4,3'-(1,2,3,6-tetrahydro-
pyridin)]-5-one hydrochloride
[0544] The compound is made from known
N-Boc-2-amino-4-iodothiophene following the general procedure via
Heck cyclisation described in Example 49.
Example 84
5-Chlorospiro[indoline-3,3'-piperidin]-2-one hydrochloride
[0545] The compound from EXAMPLE 65 was hydrogenated over Pd/C at 3
bar in ethanol. MS (TSP+) m/z [M+H.sup.+: 237.
Example 85
Spiro[indoline-3,3'-(1,3,4,7-tetrahydro-2H-azepin)]-2-one
hydrochloride
[0546] STEP A. 3-Allyl-3-[allyl(methyl)aminomethyl]-indolin-2-one.
Oxindole was acylated with ethyl acetate in the presence of sodium
ethoxide as described (Chem. Abstr. 1953, 47, p7488). The crude
product (9.16 g; 52.3 mmol) was treated with sodium hydride (56
mmol) in DMF at ice bath temperature for 30 min. Allyl bromide (51
mmol) was added and the reaction mixture left at room temperature
overnight. The crude product after workup was purified by SGC
(EtOAc/isohexanes 1:2). The acetyl group was removed by treatment
with triethylamine/water 1:1 at 65.degree. C. for 12 h and the the
3-allyloxindole thus obtained was treated with an excess of
allylmethylamine and one equivalent of paraformaldehyde in acetic
acid at 70 for 4 h. The crude material after evaporation of
solvents was partioned between DCM and basic water. SGC using
EtOAc/isohexanes 1:1 gave a reddish oil of the title product
(83%).
[0547] STEP B.
N'-Methylspiro[indoline-3,3'-(1,3,4,7-tetrahydro-2H-azepin)-
]-2-one. The product from the previous step (258 mg; 1.0 mmol) was
treated with bis(tricyclopentylphosphine)benzylidene-Ru(IV)
dichloride (104 mg; 0.14 mmol) in dry toluene under nitrogen at
60.degree. C. for three days. An additional 60 mg of the
Ru-catalyst was added and the heating continued overnight. SGC
after evaporation of solvents yielded 55 mg (21%) of the title
compound.
[0548] STEP C. t-Butyl
2-oxospiro[indoline-3,3'-(1,3,4,7-tetrahydro-2H-aze-
pine)]-1'-carboxylate. The spiro compound from STEP B (180 mg) was
demethylated by treatment with 1-chloroethyl chloroformate in
1,2-dichloroethane at reflux for 2 h followed after evaporation of
excess formiate by heating in methanol-THF-water for 1 h. The
secondary amine was bocylated by treatment with (Boc).sub.2O and
the product was chromatographed on the Kirasil TBB column using
heptane/iPrOH 9:1 as the eluent; two peaks were collected.
[0549] STEP D.
(S)-Spiro[indoline-3,3'-(1,3,4,7-tetrahydro-2H-azepin)]-2-o- ne
hydrochloride. The material from the second peak from STEP C (47
mg) was dissolved in methanol (5 ml) and treated with HCl in ether
(1.5 ml) at room temperature overnight. The title compound was
obtained upon removal of solvents. MS (TSP+) m/z [M+H].sup.+: 215.
.sup.13C NMR: (CD3OD): 181.0, 142.1, 132.7, 132.2, 130.4, 125.7,
124.8, 123.8, 111.6, 53.8, 47.6, 47.5, 35.4 ppm.
Procedure 1
Exemplified General Methods for Synthesis of Tertiary Amines by
Alkylation of a Secondary Amine
Method A
[0550] To a stirred solution of
spiro[indoline-3,3'-piperidin]-2-one and a corresponding aldehyde
or ketone (in excess) in methanol, sodiumcyanoborohydride (about 2
eq) was added. The pH was adjusted to about pH 4-6 with acetic acid
and the solution was stirred at room temp for about 18-60 h.
Concentration and extraction (EtOAc/1-2 M NH.sub.3), drying of the
combined organic phases and evaporation gave a crude product.
Purification by flash column chromatography (SiO.sub.2, eluent:
toluene/acetonitrile/triethylamine or acetone/isohexane) gave the
title compound.
Method B
[0551] To a stirred solution of a
spiro[indoline-3,3'-piperidin]-2-one in acetonitrile or DMF
potassium carbonate (1.0-1.4 equivalents) and a corresponding alkyl
halide (1.1-1.5 equivalents) was added at 0.degree. C. or room
temp. The reaction mixture was stirred at room temp--60.degree. C.
for 2-15 h. Concentration and extraction (DCM/water), drying of the
combined organic phases and evaporation gave a crude product.
Purification by flash column chromatography (SiO.sub.2, eluent:
acetone/isohexane or toluene/acetonitrile/triethylamine) gave the
title compound.
Procedure 2
Examples of Resolving Racemates by Chiral HPLC
[0552] The resolution of
1'-isopropylmethylspiro[indoline-3,3'-piperidin]-- 2-one (861 mg)
was performed by chiral HPLC on a Kirasil TBB (50.times.250 mm)
column. Eluent: heptane/1-PrOH/1-BuOH 97:2:1. About 170 mg was
loaded on the column each time and the substance was recycled twice
on the column; 370 mg of (R)-enantiomer (>99% ee) and 380 mg of
the (S)-enantiomer (93% ee) were isolated.
[0553] Other tertiary amines could be similarly separated. In most
cases it proved possible to check the enantiomeric purity of
tertiary as well as secondary amines using chiral liquid
chromatography on for example a Chiracel OD column.
[0554] It also proved possible to separate several mono-Boc
derivatives of secondary amine intermediates on the Kirasil TBB
column. One example is described in EXAMPLE 49, STEP E.
Biological Tests
[0555] 1. In Vivo Experiments
[0556] The compounds of the invention when given by systemic
injection to mice or rats, specifically reduce pain behavior in the
formalin test. This test is an accepted model of clinical pain in
man, involving elements of nociceptor activation, inflammation,
peripheral sensitization and central sensitization (A Tj.o
slashed.lsen et al. Pain 1992, 51, 5). It can therefore be inferred
that the compounds can be used as therapeutic agents to relieve
pain of various origins. The compounds of the table "Further most
preferred compounds of the invention" exhibit ED 50 doses by
subcutaneous administration to mice in the range 0.2-6 .mu.mol/kg.
The compounds of formula I also show analgesic activity in the
intraarticular FCA (Freund's complete adjuvant) test in the rat, a
model of inflammatory pain (Iadarola et al. Brain Research 1988,
455, 205-12) and in the Chung nerve lesion test in the rat, a model
for neuropathic pain (Kim and Chung. Pain 1992, 50, 355). The
analgesic effects in the animal models are obtained after doses
that do not produce tissue concentrations leading to conduction
block in nerve fibers. Thus, the analgesic effects can not be
explained by the local anesthetic properties of the compounds
mentioned in the publication by Kornet and Thio. Analgesic efficacy
after systemic administration is not a general property of drugs
with local anesthetic effects (Scott et al. British Journal of
Anaesthesia 1988, 61, 165-8).
* * * * *